CN109641895B - Indole compounds substituted with [1, 2, 4] triazolo [1, 5-a ] pyridyl - Google Patents

Indole compounds substituted with [1, 2, 4] triazolo [1, 5-a ] pyridyl Download PDF

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CN109641895B
CN109641895B CN201780052726.1A CN201780052726A CN109641895B CN 109641895 B CN109641895 B CN 109641895B CN 201780052726 A CN201780052726 A CN 201780052726A CN 109641895 B CN109641895 B CN 109641895B
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triazolo
indol
isopropyl
piperidin
pyridin
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CN109641895A (en
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A·J·迪克曼
D·S·多德
T·S·哈克
L·J·隆巴尔多
J·E·马科尔
C·P·穆萨里
L·帕索诺里
S·拉蒂娜库马尔
T·C·舍伍德
S·L·波西
R·K·西斯特拉
S·赫格德
A·拉马钱德兰
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Bristol Myers Squibb Co
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Abstract

The present application discloses compounds of formula (I) or salts thereof, wherein R1、R2、R3、R4、R5M, n and p are defined in the application. Also disclosed are methods of using such compounds as inhibitors of signaling through Toll-like receptors 7 or 8 or 9 and pharmaceutical compositions comprising such compounds. These compounds are useful in the treatment of inflammatory and autoimmune diseases.

Description

Indole compounds substituted with [1, 2, 4] triazolo [1, 5-a ] pyridyl
Cross reference to related applications
This application claims the benefit of indian provisional application 201611022328 filed on 29/6/2016 and us application 15/635,055 filed on 27/6/2017, the entire contents of which are incorporated herein by reference.
Technical Field
The present application relates generally to [1, 2, 4] triazolo [1, 5-a ] pyridyl substituted indole compounds useful as inhibitors of signaling through Toll-like receptors 7, 8 or 9(TLR7, TLR8, TLR9) or combinations thereof. Provided herein are [1, 2, 4] triazolo [1, 5-a ] pyridyl substituted indole compounds, compositions comprising such compounds, and methods of use thereof. The present application also relates to pharmaceutical compositions comprising at least one compound of the present application and methods of inhibiting the activity of a TLR in a mammal useful for treating disorders associated with TLR modulation (e.g., inflammatory and autoimmune diseases).
Toll/IL-1 receptor family members are important regulators of inflammation and host resistance. The Toll-like receptor family recognizes molecular patterns derived from infectious organisms including bacteria, fungi, parasites and viruses (reviewed in Kawai, T. et al, Nature Immunol., 11: 373-384 (2010)). Ligands that bind to the receptor induce dimerization of the adaptor molecule and recruit it to a conserved cytoplasmic motif in the receptor called the Toll/IL-1 receptor (TIR) domain. With the exception of TLR3, all TLRs recruit the adaptor molecule MyD 88. The IL-1 receptor family also contains a cytoplasmic TIR motif and recruits MyD88 upon ligand binding (reviewed in Sims, J.E. et al, Nature Rev.Immunol., 10: 89-102 (2010)).
Toll-like receptors (TLRs) are a family of transmembrane innate immune receptors that are evolutionarily conserved and involved in first-line defense. TLRs, as pattern recognition receptors, protect against foreign molecules, activated by pathogen-associated molecular patterns (PAMPs), or from tissue damage, activated by risk-associated molecular patterns (DAMPs). A total of 13 (10 in humans) TLR family members have been identified that span either the cell surface or the endosomal compartment. TLR7-9 in the group that maps to endosomes and responds to single stranded RNA (TLR7 and TLR8) or unmethylated single stranded DNA containing cytosine-phosphate-guanine (CpG) motifs (TLR 9).
Activation of TLR7/8/9 can elicit multiple inflammatory responses (cytokine production, B cell activation and IgG production, type I interferon response). In the case of autoimmune disorders, abnormally sustained activation of TLR7/8/9 leads to worsening of the disorder. Overexpression of TLR7 in mice has been shown to exacerbate autoimmune disease, and knock-out of TLR7 in mice was found to protect against disease in lupus-prone MRL/lpr mice. Double knockdown of TLR7 and 9 showed further enhanced protection.
As various disorders may benefit from treatment involving modulation of cytokines, IFN production, and B cell activity, it is apparent that new compounds capable of modulating TLR7 and/or TLR8 and/or TLR9 and methods of using these compounds may provide significant therapeutic benefit to a wide variety of patients.
The present application relates to a new class of [1, 2, 4] triazolo [1, 5-a ] pyridyl substituted indole compounds, which are found to be potent inhibitors of signaling through TLR 7/8/9. The present application provides these compounds for use as medicaments with the desired stability, bioavailability, therapeutic index and toxicity values important for their drugability.
Disclosure of Invention
The present application provides compounds of formula (I) or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, that are useful as inhibitors of signaling through Toll-like receptors 7, 8, or 9 and useful in the treatment of proliferative diseases, allergic diseases, autoimmune diseases, and inflammatory diseases.
Also provided herein are pharmaceutical compositions comprising a pharmaceutically acceptable carrier and at least one of the compounds of the present application, or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate, or prodrug thereof.
Also provided herein are methods for inhibiting Toll-like receptors 7, 8 or 9 comprising administering to a host in need of such treatment a therapeutically effective amount of a compound of the present application or at least one of a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate, or prodrug thereof.
The present application also provides methods for treating proliferative, metabolic, allergic, autoimmune, and inflammatory diseases comprising administering to a host in need of such treatment a therapeutically effective amount of a compound of the present application, or at least one of a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate, or prodrug thereof.
Also provided herein are methods of treating diseases or disorders associated with Toll-like receptor 7, 8 or 9 activity comprising administering to a mammal in need thereof a compound of formula (I) or at least one of a salt, solvate and prodrug thereof.
The present application also provides processes and intermediates useful for preparing compounds of formula (I), including salts, solvates, and prodrugs thereof.
The present application also provides at least one of a compound of formula (I) or a salt, solvate, and prodrug thereof, for use in therapy.
The present application also provides the use of a compound of formula (I) or at least one of a salt, solvate and prodrug thereof in the manufacture of a medicament for the treatment or prevention of a Toll-like receptor 7, 8 or 9 associated disorder, such as allergic, autoimmune, inflammatory and proliferative diseases.
The compounds of formula (I) and compositions comprising compounds of formula (I) are useful in the treatment, prevention or cure of various Toll-like receptor 7, 8 or 9 related disorders. Pharmaceutical compositions comprising these compounds are useful in the treatment, prevention, or slowing the progression of diseases or disorders, such as allergic, autoimmune, inflammatory, and proliferative diseases, in a variety of therapeutic areas.
These and other features of the present application will be set forth in the expanded form as the disclosure continues.
Detailed Description
In a first aspect, the present application provides at least one compound of formula (I):
Figure BDA0001979596660000031
wherein
R1Is H, Cl, -CN, C1-4Alkyl radical, C1-3Fluoroalkyl radical, C1-3Hydroxy-fluoroalkyl, -CRz＝CH2、C3-6Cycloalkyl, -CH2(C3-6Cycloalkyl), -C (O) O (C)1-3Alkyl) or tetrahydropyranyl;
each R2Independently is halogen, -CN, -OH, -NO2 +、C1-3Alkyl, -CD3、C1-2Fluoroalkyl radical, C1-2Cyanoalkyl, C1-3Hydroxyalkyl radical, C1-3Aminoalkyl, -O (CH)2)1-2OH、-(CH2)0-4O(C1-4Alkyl group), C 1-3Fluoroalkoxy, - (CH)2)1-4O(C1-3Alkyl), -O (CH)2)1-2OC(O)(C1-3Alkyl), -O (CH)2)1-2NRxRx、-C(O)O(C1-3Alkyl), -C (O) NRyRy、-NRyRy、-NRy(C1-3Fluoroalkyl group), -NRy(C1-4Hydroxyalkyl), -NRxCH2(phenyl), -NRxS(O)2(C3-6Cycloalkyl), -NR-xC(O)(C1-3Alkyl), -NR-x(CH2-cyclopropyl), C3-6Cycloalkyl, morpholinyl, dioxothiomorpholinyl, methylpiperidinyl, methylpiperazinyl, amino-oxadiazolyl, imidazolyl, triazolyl or-C (O) (thiazolyl);
R3comprises the following steps:
(a)-L1-a; or
(b)H、C1-6Alkyl radical, C1-3Fluoroalkyl radical, C1-3Cyanoalkyl radical、C1-6Hydroxyalkyl radical, C1-3Hydroxy-fluoroalkyl, -CRxRxCRx(OH)CRx＝CRxRx、-C＝N(NRxRx)、-(CRxRx)1-4O(C1-3Alkyl), - (CR)xRx)1-4O(CRxRx)1-3O(C1-3Alkyl), -CH2CH(OH)CH2O(C1-3Alkyl), - (CR)xRx)1-3S(C1-3Alkyl), - (CH)2)1-3C(O)OC(CH3)3、-(CRxRx)0-3NRxRy、-(CRxRx)0-3NRx(C1-4Hydroxyalkyl), -CH2CH(OH)CH2NRxRy、-C(O)H、-C(O)(C1-6Alkyl), -C (O) (C)1-4Hydroxyalkyl), -C (O) (C)1-3Fluoroalkyl), -C (O) (C)1-3Chloroalkyl), -C (O) (C)1-3Cyanoalkyl), - (CR)xRx)0-3C(O)OH、-C(O)(CH2)0-2O(C1-4Alkyl), -C (O) (CR)xRx)0-2O(CRxRx)1-2O(C1-3Alkyl), -C (O) (CR)xRx)0-2O(CRxRx)1-2NRyRy、-C(O)CRxRxS(O)2(C1-3Alkyl), -C (O) CRxRxNRxS(O)2(C1-3Alkyl), -C (O) CRxRxOC(O)(C1-3Alkyl), -C (O) (CR)xRx)0-3NRyRy、-C(O)(CRxRx)0-1NRx(C1-3Cyanoalkyl), -C (O) (CR)xRx)0-2NRy(C1-6Hydroxyalkyl), -C (O) (CR)xRx)0-2NRx(C1-3Fluoroalkyl), -C (O) (CR)xRx)0-1NRx(C1-5Hydroxy-fluoroalkyl), -C (O) (CR)xRx)0-1NRx(CH2)1-2O(C1-3Hydroxyalkyl), -C (O) (CR)xRx)0-2NRx(CH2)1-2NRxC(O)(C1-2Alkyl), -C (O) (CR)xRx)0-2NRx((CRxRx)1-2O(C1-2Alkyl)), -C (O) (CRxRx)0-2N((CRxRx)1-2O(C1-2Alkyl))2、-C(O)(CRxRx)0-2NRx(CRxRx)1-3NRxRx、-C(O)CRx(NH2)(CRxRx)1-4NRxRx、-C(O)CRx(NH2)(CRxRx)1-4NRxC(O)NRxRx、-C(O)(CRxRx)0-3NRx(CH2)0-1C(O)(C1-3Alkyl), -C (O) (CR)xRx)0-3N((CH2)0-1C(O)(C1-3Alkyl))2、-C(O)(CRxRx)0-1NRx(CH2)0-1C(O)(C1-3Cyanoalkyl), -C (O) (CR)xRx)0- 2NRx(CH2)1-2C(O)NRyRy、-C(O)(CRxRx)1-3C(O)NRyRy、-C(O)(CRxRx)1-3S(O)2NRyRy、-C(O)(CRxRx)0-2NRx(CHRy(CH2OH))、-(CRxRx)1-2C(O)NRyRy、-CH(CN)C(O)NRyRy、-(CRxRx)1-2C(O)NRy(C1-3Fluoroalkyl group), - (CR)xRx)1-2C(O)NRy(C1-4Hydroxyalkyl), - (CR)xRx)1-2C(O)NRy(C1-3Cyanoalkyl), - (CR)xRx)1-2C(O)NRx(CH2)1-2O(C1-3Alkyl), - (CR)xRx)1-2C(O)NRxCH(C1-4Alkyl) (C1-3Hydroxyalkyl), - (CR)xRx)1-2C(O)NRxCH(C1-3Hydroxyalkyl) (C 3-6Cycloalkyl), - (CH)2)1-2C(O)NRx(CH2)1-2C(O)NRxRx、-(CH2)1-2C(O)NRx(CH2)1-2S(C1-3Alkyl), - (CH)2)1-2C(O)NRx(CH2)1-2S(O)2OH、-(CH2)1-2C(O)NRx(CH2)1-2NRxC(O)(C1-3Alkyl), - (CH)2)1-2C(O)NRx(CH2)1-3NRxRx、-(CH2)1-2C(O)N(CH2CH3)(CH2)1- 3NRxRx、-(CRxRx)0-3S(O)2(C1-4Alkyl), - (CH)2)0-2S(O)2(C1-3Fluoroalkyl group), - (CR)xRx)0-2S(O)2NRyRy、-(CRxRx)0-2NRxS(O)2(C1-3Alkyl, -C (O) OH, -C (O) NRyRyor-C (O) NRy(CRxRx)1- 2NRyRy；
L1Is a bond, - (CR)xRx)1-2-、-(CRxRx)1-2CRx(OH)-、-(CRxRx)1-2O-、-CRxRxC(O)-、-(CRxRx)2NRx(CRxRx)0-1-、-CRxRxC(O)NRx(CRxRx)0-4-、-C(O)(CRxRx)0-3-、-C(O)(CRxRx)0-2NRx(CRxRx)0-2-、-C(O)(CRxRx)0-2N(C1-2Hydroxyalkyl) (CRxRx)0-2-、-C(O)(CRxRx)0-2NRx(CRxRx)1-2CRx(OH)-、-C(O)(CRxRx)1-2C(O)NRx-、-(CRxRx)0-2C(O)NRx(CRxRx)1-2CRx(OH)-、-(CRxRx)0-2C(O)N(C1-2Hydroxyalkyl) (CRxRx)1-2-、-C(O)(CRxRx)0-1O-、-C(O)(CRxRx)1-2NHS(O)2-、-C(O)CRx(NH2)CRxRx-、-C(O)C(O)(CRxRx)0-2-、-C(O)NRx(CRxRx)1-2-or-S (O)2-；
A is 2-oxa-6-azaspiro [3, 3 ]]Heptyl, 4-oxaspiro [2.5 ]]Octyl, 7-azaspiro [3.5 ]]Nonyl, 8-azabicyclo [3.2.1]Octyl, 8-oxa-3-azabicyclo [3.2.1]Octyl, 9-azabicyclo [3.3.1]Nonyl, adamantyl, azenyl, azetidinyl, C3-6Cycloalkyl, diazepanyl, dihydroinonyl, dihydropyrimidinonyl, dioxanyl, thiadiazinyl dioxide, thiazolidinyl dioxide, thiomorpholinyl dioxide, dioxoisothiazolidinyl, thiazinyl dioxide, dioxotetrahydrothienyl, dioxotetrahydrothiopyranyl, dioxothiomorpholinyl, furyl, imidazolyl, imidazolidinonyl, indolyl, isoquinolinyl, isoxazolyl, morpholinyl, morpholinonyl, naphthyl, octahydrocyclopenta [ b ] b]Pyranyl, octahydropyrrolo [3, 4-b ] s]Pyridyl, oxazolidone group, oxadiazolyl, oxazolyl, oxetanyl, phenyl, piperidinyl, piperidone group, piperazinyl, piperazinone group, pyrazinyl, pyrazolyl, pyridazinyl, pyridazinone group, pyridonyl, pyridyl, pyrimidinyl, pyrrolidinone group Pyrrolidinyl, pyrrolyl, quinolinyl, quinolizinyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrazolyl, thiadiazolyl, thiazolyl, triazolonyl or triazolyl, each of which is-L2-RaAnd 0 to 4RbSubstitution;
L2is a bond or-CRxRx-；
RaComprises the following steps:
(a)H、F、Cl、-CN、-OH、C1-6alkyl radical, C1-3Fluoroalkyl radical, C1-5Hydroxyalkyl, - (CH)2)0-4O(C1-3Alkyl), - (CR)xRx)1-3S(C1-3Alkyl), - (CR)xRx)1-3NHC(O)O(C1-4Alkyl), - (CR)xRx)1-3NRyRy、-(CRxRx)1-3C(O)NRyRy、-O(C1-3Fluoroalkyl), -S (O)2NRxRx、-O(CRxRx)1-3NRxRx、-NHS(O)2(C1-3Alkyl), -NR-xRx、-NRx(C1-4Alkyl), -NR-xC(O)(C1-4Alkyl), - (CR)xRx)0-3C(O)OH、-C(O)(C1-5Alkyl), -C (O) (C)1-3Fluoroalkyl), -C (O) O (C)1-4Alkyl), -C (O) NH (C)1-3Cyanoalkyl), -C (O) NRyRy、-C(O)NRxCH2C(O)NRxRxor-C (O) NRxCH2CH2NHC(O)(C1-3Alkyl groups);
(b)C3-6cycloalkyl or-C (O) NH (C)3-6Cycloalkyl), wherein each cycloalkyl is substituted with 0 to 2 substituents independently selected from: -OH, C1-3Alkyl radical, C1-3Hydroxyalkyl radical, C1-3Fluoroalkyl and-C (O) O (C)1-3Alkyl groups); or
(c)A1、-CH2A1、-C(O)A1、-NRxA1or-C (O) NRxA1Wherein A is1Is furyl, imidazolyl, indolyl, isoxazolyl, morpholinyl, octahydropyrrolo [3, 4-c ]]Pyrrolyl, oxazolyl, oxetanyl, phenyl, piperazinyl, piperidinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolyl, tetrahydrofuryl, tetrahydropyranyl, thiadiazolyl, thiazolyl, thienyl or triazolyl, each of which is substituted with 0 to 3 substituents independently selected from: -OH, C 1-3Alkyl radical, C1-3Hydroxyalkyl, -C (O) (C)1-2Alkyl), -C (O) O (C)1-3Alkyl), -NR-xRxPhenyl, trifluoromethyl-phenyl, -CH2(bromophenyl) and-CH2CH2(pyrrolidinyl);
each RbIndependently F, -OH, -CH3、-CF3or-OCH3；
Each RxIndependently is H or-CH3；
Each RyIndependently is H or C1-6An alkyl group;
Rzis H, C1-2Alkyl or C1-2A fluoroalkyl group;
each R4Independently F, -OH, C1-2Alkyl or-OCH3(ii) a Or two R attached to the same carbon atom4To form ═ O; or wherein when m is at least 2, two R are each attached to a different carbon atom adjacent to the nitrogen atom in the piperidinyl ring4Can form-CH2CH2-a bridge;
each R5Independently F, Cl, -CN, C1-2Alkyl radical, C1-2Fluoroalkyl or-OCH3；
m is 0, 1, 2, 3 or 4;
n is 0, 1 or 2; and is
p is 0, 1, 2, 3 or 4.
In a second aspect, the present application provides at least one compound of formula (I) or a salt thereof, wherein
R1Is H, Cl, -CN, C1-4Alkyl radical, C1-3Fluoroalkyl radical, C1-3Hydroxy-fluoroalkyl, -CRz＝CH2、C3-6Cycloalkyl, -CH2(C3-6Cycloalkyl), -C (O) O (C)1-3Alkyl) or tetrahydropyranyl;
each R2Independently is halogen, -CN, -OH, -NO2 +、C1-3Alkyl radical, C1-2Fluoroalkyl radical, C1-3Hydroxyalkyl radical, C1-3Aminoalkyl, - (CH)2)0-4O(C1-3Alkyl group), C1-3Fluoroalkoxy radical, C2-4Alkoxyalkoxy, -O (CH)2)1-2NRxRx、-C(O)O(C1-3Alkyl), -C (O) NRyRy、-NRyRy、-NRxC(O)(C1-3Alkyl), -NR- x(CH2-cyclopropyl), C3-6Cycloalkyl, methylpiperidinyl, methylpiperazinyl, amino-oxadiazolyl, imidazolyl, triazolyl or-C (O) (thiazolyl);
R3comprises the following steps:
(a)-L1-a; or
(b)H、C1-6Alkyl radical, C1-3Fluoroalkyl radical, C1-3Cyanoalkyl, C1-6Hydroxyalkyl radical, C1-3Hydroxy-fluoroalkyl, -CRxRxCRx(OH)CRx＝CRxRx、-(CRxRx)1-4O(C1-3Alkyl), - (CR)xRx)1-4O(CRxRx)1-3O(C1-3Alkyl), -CH2CH(OH)CH2O(C1-3Alkyl), - (CR)xRx)1-3S(C1-3Alkyl), - (CH)2)1-3C(O)OC(CH3)3、-(CRxRx)0-3NRxRy、-(CRxRx)0-3NRx(C1-4Hydroxyalkyl), -CH2CH(OH)CH2NRxRy、-C(O)H、-C(O)(C1-6Alkyl), -C (O) (C)1-3Hydroxyalkyl), -C (O) (C)1-3Fluoroalkyl), -C (O) (C)1-3Chloroalkyl), -C (O) (C)1-3Cyanoalkyl radicals)-(CRxRx)0-3C(O)OH、-C(O)(CH2)0-2O(C1-4Alkyl), -C (O) (CR)xRx)0-2O(CRxRx)1-2O(C1-3Alkyl), -C (O) CRxRxS(O)2(C1-3Alkyl), -C (O) CRxRxNRxS(O)2(C1-3Alkyl), -C (O) CRxRxOC(O)(C1-3Alkyl), -C (O) (CR)xRx)0-3NRyRy、-C(O)(CRxRx)0-1NRx(C1-3Cyanoalkyl), -C (O) (CR)xRx)0-2NRy(C1-6Hydroxyalkyl), -C (O) (CR)xRx)0-1NRx(C1-3Fluoroalkyl), -C (O) (CR)xRx)0-1NRx(C1-5Hydroxy-fluoroalkyl), -C (O) (CR)xRx)0-1NRx(CH2)1-2O(C1-3Hydroxyalkyl), -C (O) (CR)xRx)0-1NRx(CH2)1-2NRxC(O)(C1-2Alkyl), -C (O) (CR)xRx)0-1NRx((CRxRx)1-2O(C1-2Alkyl)), -C (O) CRx(NH2)(CRxRx)1-4NRxRx、-C(O)CRx(NH2)(CRxRx)1-4NRxC(O)NRxRx、-C(O)(CRxRx)0-3NRx(CH2)0-1C(O)(C1-3Alkyl), -C (O) (CR)xRx)0-1NRx(CH2)0-1C(O)(C1-3Cyanoalkyl), -C (O) (CR)xRx)0-1NRx(CH2)1-2C(O)NRyRy、-C(O)(CRxRx)1-3C(O)NRyRy、-C(O)(CRxRx)0-1NRx(CHRy(CH2OH))、-(CRxRx)1-2C(O)NRyRy、-(CRxRx)1-2C(O)NRy(C1-3Fluoroalkyl group), - (CR)xRx)1-2C(O)NRy(C1-4Hydroxyalkyl), - (CR)xRx)1-2C(O)NRy(C1-3Cyanoalkyl), - (CR)xRx)1-2C(O)NRx(CH2)1-2O(C1-3Alkyl), - (CR)xRx)1-2C(O)NRxCH(C1-4Alkyl) (C1-3Hydroxyalkyl), - (CH)2)1-2C(O)NRx(CH2)1-2C(O)NRxRx、-(CH2)1-2C(O)NRx(CH2)1-2S(O)2OH、-(CH2)1-2C(O)NRx(CH2)1-2NRxC(O)(C1-3Alkyl), - (CH)2)1-2C(O)NRx(CH2)1-3NRxRx、-(CH2)1-2C(O)N(CH2CH3)(CH2)1-3NRxRx、-(CH2)0-2S(O)2(C1-4Alkyl), - (CH)2)0- 2S(O)2(C1-3Fluoroalkyl group), - (CH)2)0-2S(O)2NRxRx、-C(O)C(O)OH、-C(O)C(O)NRyRyor-C (O) NRy(CRxRx)1-2NRyRy；
L1Is a bond, - (CR)xRx)1-2-、-(CRxRx)1-2CRx(OH)-、-(CRxRx)1-2O-、-CRxRxC(O)-、-(CRxRx)2NRx(CRxRx)0-1-、-CRxRxC(O)NRx(CRxRx)0-4-、-C(O)(CRxRx)0-3-、-C(O)(CRxRx)0-2NRx(CRxRx)0-2-、-C(O)(CRxRx)0-2N(C1-2Hydroxyalkyl) (CRxRx)0-2-、-C(O)(CRxRx)0-2NRx(CRxRx)1-2CRx(OH)-、-C(O)(CRxRx)1-2C(O)NRx-、-(CRxRx)0-2C(O)NRx(CRxRx)1-2CRx(OH)-、-(CRxRx)0-2C(O)N(C1-2Hydroxyalkyl) (CRxRx)1-2-、-C(O)(CRxRx)0-1O-、-C(O)(CRxRx)1-2NHS(O)2-、-C(O)CRx(NH2)CRxRx-、-C(O)C(O)(CRxRx)0-2-、-C(O)NRx(CRxRx)1-2-or-S (O)2-；
A is 2-oxa-6-azaspiro [3, 3 ]]Heptyl, 4-oxaspiro [2.5 ]]Octyl, 7-azaspiro [3.5 ]]Nonyl, 8-azabicyclo [3.2.1 ]Octyl, 8-oxa-3-azabicyclo [3.2.1]Octyl, 9-azabicyclo [3.3.1]Nonyl, adamantyl, azenyl, azetidinyl, C3-6Cycloalkyl, diazepanyl, dihydroinonyl, dihydropyrimidinonyl, thiadiazinyl dioxide, isothiazolidinyl dioxide, thiazinyl dioxide, dioxotetrahydrothienyl, dioxotetrahydrothiopyranyl, dioxothiomorpholinyl, furyl, imidazolyl, imidazolidinonyl, indolyl, isoquinolinyl, isoxazolyl, morpholinyl, morpholinonyl, naphthyl, octahydrocyclopenta [ b ] alkyl]Pyranyl, oxazolidonyl, oxadiazolyl, oxetanyl, oxazolyl, phenyl, piperidinyl, piperidinonyl, piperazinyl, piperazinonyl, pyrazinyl, pyrazolyl, pyridazinonyl, pyridonyl, pyridinyl, pyrimidinyl, pyrrolidinonyl, pyrrolidinyl, pyrrolyl, quinolinyl, quinolizinonyl, tetrahydrofuranyl, tetrahydropyranoylA radical, tetrazolyl, thiadiazolyl, thiazolyl or triazolyl, each of said radicals being-L2-RaAnd 0 to 4RbSubstitution;
L2is a bond or-CRxRx-；
RaComprises the following steps:
(a)H、F、Cl、-CN、-OH、C1-6alkyl radical, C1-3Fluoroalkyl radical, C1-5Hydroxyalkyl, - (CH)2)0-4O(C1-3Alkyl), - (CR)xRx)1-3S(C1-3Alkyl), - (CR)xRx)1-3NHC(O)O(C1-4Alkyl), - (CR) xRx)1-3NRyRy、-(CRxRx)1-3C(O)NRyRy、-O(C1-3Fluoroalkyl), -S (O)2NRxRx、-O(CRxRx)1-3NRxRx、-NHS(O)2(C1-3Alkyl), -NR-xRx、-NRx(C1-4Alkyl), -NR-xC(O)(C1-4Alkyl), - (CR)xRx)0-3C(O)OH、-C(O)(C1-5Alkyl), -C (O) (C)1-3Fluoroalkyl), -C (O) O (C)1-4Alkyl), -C (O) NH (C)1-3Cyanoalkyl), -C (O) NRyRy、-C(O)NRxCH2C(O)NRxRxor-C (O) NRxCH2CH2NHC(O)(C1-3Alkyl groups);
(b)C3-6cycloalkyl or-C (O) NH (C)3-6Cycloalkyl), wherein each cycloalkyl is substituted with 0 to 2 substituents independently selected from: -OH, C1-3Alkyl radical, C1-3Hydroxyalkyl radical, C1-3Fluoroalkyl and-C (O) O (C)1-3Alkyl groups); or
(c)A1、-CH2A1、-C(O)A1、-NRxA1or-C (O) NRxA1Wherein A is1Is furyl, imidazolyl, indolyl, isoxazolyl, morpholinyl, octahydropyrrolo [3, 4-c ]]Pyrrolyl, oxazolyl, oxetanyl, phenyl, piperazinyl, piperidinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolyl, tetrahydrofuryl, tetrahydropyranyl, thiadiazolyl, thiazolyl, thienyl or triazolyl, each of which is substituted with 0 to 3 substituents independently selected from: -OH, C1-3Alkyl radical, C1-3Hydroxyalkyl, -C (O) (C)1-2Alkyl), -C (O) O (C)1-3Alkyl), -NR-xRxPhenyl, trifluoromethyl-phenyl, -CH2(bromophenyl) and-CH2CH2(pyrrolidinyl);
each RbIndependently of each other are F, -CH3、-CF3or-OCH3；
Each RxIndependently is H or-CH3；
Each RyIndependently is H or C1-6An alkyl group;
Rzis H, C1-2Alkyl or C1-2A fluoroalkyl group;
each R 4Independently F, -OH, C1-2Alkyl or-OCH3(ii) a Or two R attached to the same carbon atom4To form ═ O;
each R5Independently F, Cl, -CN, C1-2Alkyl radical, C1-2Fluoroalkyl or-OCH3；
m is 0, 1, 2, 3 or 4;
n is 0, 1 or 2; and is
p is 0, 1, 2, 3 or 4.
One embodiment provides a compound of formula (I) or a salt thereof, wherein R1Is H, Cl, -CN, C1-4Alkyl radical, C1-3Fluoroalkyl radical, C1-3Hydroxy-fluoroalkyl, C3-6Cycloalkyl, -CH2(C3-6Cycloalkyl) or tetrahydropyranyl; and R is2、R3、R4、R5M, n and p are as defined in the first or second aspect. In this embodiment include those wherein R1Is H, Cl, -CN, C1-4Alkyl or C1-2A compound of fluoroalkyl group. Also included are those in which R1is-CH2CH3、-CH(CH3)2or-CH2CHF2A compound of (1); and wherein R1is-CH (CH)3)2The compound of (1). Also included are compounds wherein m is 0 and n is 0.
One embodiment provides a compound of formula (I) or a salt thereof, wherein each R2Independently F, Cl, -CN, -OH, C1-3Alkyl, -CD3、C1-2Fluoroalkyl radical, C1-3Hydroxyalkyl radical, C1-2Cyanoalkyl, C1-3Aminoalkyl radical, C1-4Alkoxy radical, C1-2Fluoroalkoxy, -O (CH)2)1-2OH、-(CH2)1-4O(C1-3Alkyl), -O (CH)2)1-2OC(O)(C1-3Alkyl), -O (CH)2)1-2NRxRx、-C(O)O(C1-3Alkyl), -C (O) NRyRy、-NRyRy、-NRy(C1-3Fluoroalkyl group), -NRy(C1-4Hydroxyalkyl), -NRxCH2(phenyl), -NRxS(O)2(C3-6Cycloalkyl), C3-6Cycloalkyl, -NRxC(O)(C1-3Alkyl), -NR- x(CH2-cyclopropyl), C3-6Cycloalkyl, morpholinyl, dioxothiomorpholinyl, methylpiperidinyl, methylpiperazinyl, amino-oxadiazolyl, imidazolyl, triazolyl or-C (O) (thiazolyl); and R is1、R3、R4、R5、Rx、RyM, n and p are as defined in the first or second aspect. Included in this embodiment are compounds wherein each R is2Independently F, Cl, -CN, C1-3Alkyl, -CD3、C1-2Fluoroalkyl radical, C1-3Hydroxyalkyl radical, C1-2Cyanoalkyl, C1-4Alkoxy radical, C1-2Fluoroalkoxy, -O (CH)2)1-2OH、-(CH2)1-4O(C1-3Alkyl), -O (CH)2)1-2OC(O)(C1-3Alkyl), -NR-yRy、-NRy(C1-3Fluoroalkyl group), -NRy(C1-4Hydroxyalkyl), -NRxCH2(phenyl), -NRxS(O)2(C3-6Cycloalkyl), C3-6Cycloalkyl, morpholinyl, dioxothiomorpholinyl or methylpiperazinyl. Also included in this embodiment are compounds wherein each R is2Independently of each other is F, Cl, -CN, -CH3、-CH2CH3、-CH(CH3)2、-CD3、-CF3、-CH2CN、-CH2OH、-CH2CH2OH、-CH(CH3)OH、-C(CH3)2OH、-OCH2CH2OH、-OCH3、-OCH2CH3、-OCH2CH(CH3)2、-OCHF2、-CH2OCH3、-CH2OCH2CH3、-OCH2CH2OC(O)CH3、-NH2、-NH(CH2CH3)、-NH(CH2CF3)、-NH(CH2C(CH3)2OH)、-NHCH2(phenyl), -NHS (O)2(cyclopropyl), cyclopropyl, morpholinyl, dioxothiomorpholinyl or methylpiperazinyl.
One embodiment provides a compound of formula (I) or a salt thereof, wherein each R2Independently of one another is halogen, -CN, C1-3Alkyl, -CD3、C1-2Fluoroalkyl radical, C1-2Cyanoalkyl, C1-3Hydroxyalkyl, -O (CH)2)1-2OH、-(CH2)0-4O(C1-4Alkyl group), C1-3Fluoroalkoxy, -O (CH)2)1And R is1、R3、R4、R5、Rx、RyM, n and p are as defined in the first or second aspect. Included in this embodiment are compounds wherein 2OC(O)(C1-3Alkyl), -NR-yRy、-NRy(C1-3Fluoroalkyl group), -NRy(C1-4Hydroxyalkyl), -NRxCH2(phenyl), -NRxS(O)2(C3-6Cycloalkyl), C3-6Cycloalkyl radical, doMorpholinyl, dioxothiomorpholinyl or methylpiperazinyl; and R is1、R3、R4、R5、Rx、RyM, n and p are as defined in the first or second aspect. Included in this embodiment are compounds wherein each R is2Independently F, Cl, -CN, -OH, C1-3Alkyl, -CD3、C1-2Fluoroalkyl radical, C1-2Cyanoalkyl, C1-3Hydroxyalkyl, -O (CH)2)1-2OH、-O(C1-4Alkyl group), C1-2Fluoroalkoxy, - (CH)2)1-4O(C1-3Alkyl), -O (CH)2)1-2OC(O)(C1-3Alkyl), -NR-yRy、-NRy(C1-3Fluoroalkyl group), -NRy(C1-4Hydroxyalkyl), -NRxCH2(phenyl), -NRxS(O)2(C3-6Cycloalkyl), C3-6Cycloalkyl, morpholinyl, dioxothiomorpholinyl or methylpiperazinyl. Also included are compounds wherein m is 0 and n is 0.
One embodiment provides a compound of formula (I) or a salt thereof, wherein R2Is F, Cl, -CN, C1-2Alkyl, -CD3、-CF3、-CH2OH、-C(CH3)2OH、-OCH3、-CH2OCH3、-OCH2CH3Cyclopropyl or morpholinyl; and R is1、R3、R4、R5M, n and p are as defined in the first or second aspect. In this embodiment include wherein each R is2Independently is-CH3or-OCH3The compound of (1). Also included are compounds wherein m is 0 and n is 0.
One embodiment provides a compound of formula (I) or a salt thereof, wherein R3is-L1-a; and R is1、R2、R4、R5、L1And a is defined in the first aspect or the second aspect. Included in this embodiment are compounds wherein L 1Is a bond, - (CR)xRx)1-2-、-(CRxRx)1-2CRx(OH)-、-(CRxRx)1-2O-、-CRxRxC(O)-、-(CRxRx)2NRx(CRxRx)0-1-、-CRxRxC(O)NRx(CRxRx)0-4-、-C(O)(CRxRx)0-3-、-C(O)(CRxRx)0-2NRx(CRxRx)0-2-、-C(O)(CRxRx)0-2N(C1-2Hydroxyalkyl) (CRxRx)0-2-、-C(O)(CRxRx)1-2C(O)NRx-、-C(O)(CRxRx)0-2NRx(CRxRx)1-2CRx(OH)-、-(CRxRx)0-2C(O)NRx(CRxRx)1-2CRx(OH)-、-(CRxRx)0-2C(O)N(C1-2Hydroxyalkyl) (CRxRx)1-2-、-C(O)(CRxRx)0-1O-、-C(O)(CRxRx)1-2NHS(O)2-、-C(O)CRx(NH2)CRxRx-、-C(O)C(O)(CRxRx)0-2-、-C(O)NRx(CRxRx)1-2-or-S (O)2-. Also includes wherein L1Is a bond, -CRxRx-、-CRxRxC(O)-、-CRxRxC(O)NRx-or-C (O) (CR)xRx)0-2-a compound of (a). Also included are compounds wherein m is 0 and n is 0.
One embodiment provides a compound of formula (I) or a salt thereof, wherein R3is-L1-A；L1Is a bond, -CRxRx-、-CRxRxC(O)-、-CRxRxC(O)NRx-or-C (O) (CR)xRx)0-2-; a is a ring selected from: azetidinyl, C3-6Cycloalkyl, dioxotetrahydrothiopyranyl, dioxolyl, and/or thioxanthyl,Thiadiazinyl dioxide, morpholinyl sulfur dioxide, furyl, imidazolyl, isoquinolinyl, morpholinyl, oxazolyl, 2-oxa-6-azaspiro [3.3]Heptyl, oxetanyl, phenyl, piperazinyl, piperidinyl, pyrazinyl, pyrazolyl, pyridinyl, pyrrolidinyl, pyrrolyl, quinolinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrazolyl, thiadiazolyl, thiazolyl and triazolyl, each of which is-L2-RaAnd 0 to 4RbSubstitution; and R is1、R2、R4、R5、Rx、L2、RaM, n and p are as defined in the first or second aspect. Included in this embodiment are compounds wherein L2Is a bond or-CRxRx-; and R isaIs (a) H, -CN, -OH, C1-3Alkyl radical, C1-2Fluoroalkyl radical, C1-3Hydroxyalkyl, - (CH)2)1-2O(C1-3Alkyl), - (CR)xRx)1-3NHC(O)O(C1-4Alkyl), - (CR)xRx)1-3NH2、-(CRxRx)1-3NRx(C1-4Alkyl), -O (C)1-2Fluoroalkyl), -S (O) 2NRxRx、-NHS(O)2(C1-3Alkyl), -NR-xRx、-NRx(C1-4Alkyl), - (CR)xRx)1-2C(O)OH、-C(O)OH、-C(O)(C1-3Alkyl), -C (O) O (C)1-3Alkyl), -C (O) NRx(C1-2Alkyl), -C (O) N (C)1-3Alkyl radical)2、-C(O)NRxCH2C(O)NRxRxor-C (O) NRxCH2CH2NHC(O)(C1-3Alkyl groups); (b) c3-6Cycloalkyl or-C (O) NH (C)3-6Cycloalkyl), wherein each cycloalkyl is substituted with 0 to 2 substituents independently selected from: -OH, C1-3Alkyl radical, C1-3Hydroxyalkyl radical, C1-3Fluoroalkyl and-C (O) O (C)1-3Alkyl groups); or (c) A1、-CH2A1、-C(O)A1or-C (O) NHA1Wherein A is1Is furyl, imidazolyl, indolyl, isoxazolyl, octahydropyrrolo [3, 4-c ]]Pyrrolyl, oxazolyl, oxetanyl, phenyl, piperazinyl, piperidinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolyl, tetrahydrofuryl, tetrahydropyranyl, thiadiazolyl, thiazolyl, thienyl or triazolyl, each of which is substituted with 0 to 3 substituents independently selected from: -OH, C1-3Alkyl radical, C1-3Hydroxyalkyl, -C (O) (C)1-2Alkyl), -C (O) O (C)1-3Alkyl), -NR-xRxPhenyl, trifluoromethyl-phenyl, -CH2(bromophenyl) and-CH2CH2(pyrrolidinyl). Also included are compounds wherein m is 0 and n is 0.
One embodiment provides a compound of formula (I) or a salt thereof, wherein R3Is H, C1-6Alkyl radical, C1-3Fluoroalkyl radical, C1-3Cyanoalkyl, C1-6Hydroxyalkyl radical, C1-3Hydroxy-fluoroalkyl, -CR xRxCRx(OH)CRx＝CRxRx、-C＝N(NRxRx)、-(CRxRx)1-4O(C1-3Alkyl), - (CR)xRx)1-4O(CRxRx)1-3O(C1-3Alkyl), -CH2CH(OH)CH2O(C1-3Alkyl), - (CR)xRx)1-3S(C1-3Alkyl), - (CH)2)1-3C(O)OC(CH3)3、-(CRxRx)0-3NRxRy、-(CRxRx)0-3NRx(C1-4Hydroxyalkyl), -CH2CH(OH)CH2NRxRy、-C(O)H、-C(O)(C1-6Alkyl), -C (O) (C)1-4Hydroxyalkyl), -C (O) (C)1-3Fluoroalkyl), -C (O) (C)1-3Chloroalkyl), -C (O) (C)1-3Cyanoalkyl), - (CR)xRx)0-3C(O)OH、-C(O)(CH2)0-2O(C1-4Alkyl), -C (O) (CR)xRx)0- 2O(CRxRx)1-2O(C1-3Alkyl), -C (O) (CR)xRx)0-2O(CRxRx)1-2NRyRy、-C(O)CRxRxS(O)2(C1-3Alkyl), -C (O) CRxRxNRxS(O)2(C1-3Alkyl), -C (O) CRxRxOC(O)(C1-3Alkyl), -C (O) (CR)xRx)0-3NRyRy、-C(O)(CRxRx)0-1NRx(C1-3Cyanoalkyl), -C (O) (CR)xRx)0-2NRy(C1-6Hydroxyalkyl), -C (O) (CR)xRx)0-2NRx(C1-3Fluoroalkyl), -C (O) (CR)xRx)0-1NRx(C1-5Hydroxy-fluoroalkyl), -C (O) (CR)xRx)0-1NRx(CH2)1-2O(C1-3Hydroxyalkyl), -C (O) (CR)xRx)0-2NRx(CH2)1-2NRxC(O)(C1-2Alkyl), -C (O) (CR)xRx)0-2NRx((CRxRx)1-2O(C1-2Alkyl)), -C (O) (CRxRx)0-2N((CRxRx)1-2O(C1-2Alkyl))2、-C(O)(CRxRx)0-2NRx(CRxRx)1-3NRxRx、-C(O)CRx(NH2)(CRxRx)1-4NRxRx、-C(O)CRx(NH2)(CRxRx)1-4NRxC(O)NRxRx、-C(O)(CRxRx)0-3NRx(CH2)0-1C(O)(C1-3Alkyl), -C (O) (CR)xRx)0-3N((CH2)0-1C(O)(C1-3Alkyl))2、-C(O)(CRxRx)0-1NRx(CH2)0-1C(O)(C1-3Cyanoalkyl), -C (O) (CR)xRx)0-2NRx(CH2)1-2C(O)NRyRy、-C(O)(CRxRx)1-3C(O)NRyRy、-C(O)(CRxRx)1-3S(O)2NRyRy、-C(O)(CRxRx)0-2NRx(CHRy(CH2OH))、-(CRxRx)1-2C(O)NRyRy、-CH(CN)C(O)NRyRy、-(CRxRx)1-2C(O)NRy(C1-3Fluoroalkyl group), - (CR)xRx)1-2C(O)NRy(C1-4Hydroxyalkyl), - (CR)xRx)1-2C(O)NRy(C1-3Cyanoalkyl), - (CR)xRx)1-2C(O)NRx(CH2)1-2O(C1-3Alkyl), - (CR)xRx)1-2C(O)NRxCH(C1-4Alkyl) (C1-3Hydroxyalkyl), - (CH)2)1-2C(O)NRx(CH2)1-2C(O)NRxRx、-(CH2)1-2C(O)NRx(CH2)1-2S(C1-3Alkyl), - (CH)2)1-2C(O)NRx(CH2)1-2S(O)2OH、-(CH2)1-2C(O)NRx(CH2)1-2NRxC(O)(C1-3Alkyl), - (CH)2)1-2C(O)NRx(CH2)1-3NRxRx、-(CH2)1-2C(O)N(CH2CH3)(CH2)1-3NRxRx、-(CRxRx)0-3S(O)2(C1-4Alkyl), - (CH)2)0-2S(O)2(C1-3Fluoroalkyl group), - (CR)xRx)0-2S(O)2NRyRy、-(CRxRx)0-2NRxS(O)2(C1-3Alkyl, -C (O) OH, -C (O) NRyRyor-C (O) NRy(CRxRx)1-2NRyRy(ii) a And R is1、R2、R4、R5、Rx、RyM, n and p are as defined in the first or second aspect. Also included are compounds wherein m is 0 and n is 0.
One embodiment provides a compound of formula (I) or a salt thereof, wherein R3Is H, C1-6Alkyl radical, C1-3Fluoroalkyl radical, C1-3Cyanoalkyl, C1-5Hydroxyalkyl, -C ═ N (NR)xRx)、-(CRxRx)1-2O(C1-2Alkyl), - (CR)xRx)1-4O(CRxRx)1-3O(C1-3Alkyl), -CH2CH(OH)CH2O(C1-3Alkyl), - (CR)xRx)1-3S(C1-3Alkyl), - (CH) 2)1-3C(O)OC(CH3)3、-(CRxRx)0- 3NRxRy、-(CRxRx)0-3NRx(C1-4Hydroxyalkyl), -CH2CH(OH)CH2NRxRy、-C(O)(C1-6Alkyl), -C (O) (C)1-4Hydroxyalkyl), -C (O) (C)1-3Fluoroalkyl), -C (O) (C)1-3Chloroalkyl), -C (O) (C)1-3Cyanoalkyl), - (CR)xRx)0-3C(O)OH、-C(O)(CH2)0-2O(C1-4Alkyl), -C (O) (CR)xRx)0-2O(CRxRx)1-2O(C1-3Alkyl), -C (O) (CH)2)0-2O(CH2)1-2HRyRy、-C(O)CRxRxS(O)2(C1-2Alkyl), -C (O) CRxRxNRxS(O)2(C1-2Alkyl), -C (O) CRxRxOC(O)(C1-3Alkyl), -C (O) (CR)xRx)0-2NRyRy、-C(O)(CRxRx)0-2NRx(C1-2Cyanoalkyl), -C (O) (CR)xRx)0-2NRy(C1-6Hydroxyalkyl), -C (O) (CR)xRx)0-2NRx(C1-3Fluoroalkyl), -C (O) (CR)xRx)0-1NRx(C1-5Hydroxy-fluoroalkyl), -C (O) (CR)xRx)0-1NRx((CRxRx)1-2O(C1-2Alkyl)), -C (O) (CRxRx)0-1NRx(CH2)1-2O(C1-3Hydroxyalkyl), -C (O) (CR)xRx)0-1NRx(CH2)1-2NRxC(O)(C1-2Alkyl), -C (O) (CR)xRx)0-2NRx((CRxRx)1-2O(C1-2Alkyl)), -C (O) (CRxRx)0-1NRx(CRxRx)1-3NRxRx、-C(O)CRx(NH2)(CRxRx)1-4NRxRx、-C(O)CRx(NH2)(CRxRx)1- 4NRxC(O)NRxRx、-C(O)(CRxRx)0-3NRx(CH2)0-1C(O)(C1-3Alkyl), -C (O) (CR)xRx)0-1NRx(CH2)0-1C(O)(C1-3Cyanoalkyl), -C (O) (CR)xRx)0-2NRx(CH2)1-2C(O)NRyRy、-C(O)(CRxRx)0-2NRx(CHRy(CH2OH))、-(CRxRx)1-2C(O)NRyRy、-(CRxRx)1-2C(O)NRy(C1-3Fluoroalkyl group), - (CR)xRx)1-2C(O)NRy(C1-4Hydroxyalkyl), - (CR)xRx)1-2C(O)NRx(C1-3Cyanoalkyl), -CH (CN) C (O) NRyRy、-(CRxRx)1-2C(O)NRx(CH2)1-2O(C1-3Alkyl), - (CR)xRx)1-2C(O)NRxCH(C1-4Alkyl) (C1-3Hydroxyalkyl), - (CH)2)1-2C(O)NRx(CH2)1-2C(O)NRxRx、-(CH2)1-2S(O)2NRx(CH2)1-2S(C1-2Alkyl), - (CH)2)1-2C(O)NRx(CH2)1-2S(O)2OH、-(CH2)1-2C(O)NRx(CH2)1-2NRxC(O)(C1-3Alkyl), - (CH)2)1-2C(O)NRx(CH2)1-3NRxRx、-(CH2)1-2C(O)N(CH2CH3)(CH2)1- 3NRxRx、-(CRxRx)1-3S(O)2(C1-4Alkyl), - (CH)2)0-2S(O)2(C1-3Fluoroalkyl group), - (CH)2)1-2S(O)2NRyRy、-C(O)C(O)OH、-C(O)C(O)NRyRyor-C (O) NRy(CRxRx)1-2NRyRy(ii) a And R is1、R2、R4、R5M, n and p are as defined in the first or second aspect. Also included are compounds wherein m is 0 and n is 0.
One embodiment provides a compound of formula (I) or a salt thereof, wherein R3is-C (O) CH2(2-oxa-6-azaspiro [3.3 ]]Heptyl), -C (O) CH2(piperazinonyl), -C (O) CH2(piperazinyl), -C (O) CH2(piperidinyl), -C (O) CH2(pyrimidinyl), -C (O) CH2(pyrrolidinyl), -C (O) CH2(tetrahydropyranyl) -, -C (O) CH2(tetrazolyl), -C (O) CH 2(thiazolyl), -C (O) CH2CH2(azepanyl), -C (O) CH2CH2(azetidinyl), -C (O) CH2CH2(dioxothiomorpholinyl), -C (O) CH2CH2(morpholinyl), -C (O) CH2CH2(piperidonyl), -C (O) CH2CH2(piperidinyl), -C (O) CH2CH2(pyrrolidinonyl), -C (O) CH2CH2(pyrrolidinyl), -C (O) CH2CH(CH3) (oxetanyl), -C (O) NH (piperidinyl), -C (O) NH (pyrrolidinyl), -C (O) CH2NH (cyclopropyl), -C (O) CH2NH (cyclobutyl), -C (O) CH2NH (cyclohexyl), -C (O) CH2NH (oxetanyl), -C (O) CH2N(CH3) (cyclopropyl), -C (O) CH2N(CH3) (cyclohexyl), -C (O) CH2CH2NH (cyclopentyl), -C (O) CH2CH2NH (cyclohexyl), -C (O) CH2CH2N(CH3) (cyclohexyl), -C (O) CH2N(CH2CH2OH) (cyclopropyl), -C (O) CH2CH2N(CH2CH2OH) (cyclopropyl), -C (O) CH2CH2NH(CH2(cyclopropyl)), -C (O) CH2CH2NH(CH2(tetrahydrofuryl)), -C (O) CH2NH(CH2(cyclopropyl)), -C (O) CH2NH(CH2(cyclohexyl)), -C (O) CH2NH(CH2(tetrahydrofuryl)), -C (O) NH (CH)2(piperidinyl)), -C (O) NH (CH)2(pyrrolidinyl)), -C (O) NH (CH)2CH2(morpholinyl)), -C (O) NH (CH)2CH2(piperazinyl)), -C (O) NH (CH)2CH2(piperidinyl)), -C (O) NH (CH)2CH2(pyrrolidinyl)), -C (O) O (azetidinyl), -C (O) O (piperidinyl), -C (O) O (pyrrolidinyl), -C (O) OCH2(azetidinyl), -C (O) OCH2(piperidinyl), -C (O) OCH2(pyrrolidinyl), -C (O) OCH2CH2(dioxothiomorpholinyl), -C (O) OCH 2CH2(imidazolyl), -C (O) OCH2CH2(morpholinyl), -C (O) OCH2CH2(piperazinyl), -C (O) OCH2CH2(piperidinyl), -C (O) OCH2CH2(pyrrolidinyl), -CH2(cyclopropyl), -CH2(dioxotetrahydrothiopyran group), -CH2(imidazolyl), -CH2(isoxazolyl), -CH2(morpholinyl), -CH2(oxadiazolyl), -CH2(oxazolyl), -CH2(oxetanyl), -CH2(phenyl), -CH2(pyrazinyl), -CH2(pyrazolyl), -CH2(pyridazinyl), -CH2(pyrimidinyl), -CH2(tetrazolyl), -CH2(thiadiazolyl), -CH2(thiazolyl), -CH2(triazolonyl), -CH2(triazolyl), -CH (CH)3) (pyrazolyl), -CH (CH)3) (pyridazinyl), -CH (CH)3) (pyrimidinyl), -CH2CH2(dioxoisothiazolidinyl), -CH (CN) (oxetanyl), -CH (CH)3)CH2S(O)2(morpholinyl), -CH (CH)3)CH2S(O)2(piperidinyl), -CH2C (O) (morpholinyl), -CH2C (O) (2-oxa-6-azaspiro [3.3 ]]Heptyl), -CH2C (O) (azetidinyl), -CH2C (O) (thiadiazinyl dioxide), -CH2C (O) (thiazolidinyl dioxide), -CH2C (O) (thiomorpholinyl sulfate), -CH2C (O) (dioxothiomorpholinyl), -CH2C (O) (2-oxa-6-azaspiro [3.3 ]]Heptyl), -CH2C (O) (piperazinonyl), -CH2C (O) (piperazinyl), -CH2C (O) (piperidinyl), -CH2C (O) (pyrrolidinyl), -CH2C(O)NHCH(CH2CH2OH) (cyclopropyl), -CH 2C(O)N(CH2CH2OH) (cyclopropyl), -CH2C(O)N(CH3) (cyclopropyl), -CH2C(O)N(CH3) (tetrahydrofuryl), -CH2C(O)N(CH3) (tetrahydropyranyl) -, -CH2C(O)N(CH3)CH2CH2(cyclopentyl), -CH2C(O)N(CH3)CH2CH2(pyrazolyl), -CH2C (O) NH (azetidinyl), -CH2C(O)NH(CH2(oxetanyl)), -CH2C (O) NH (cyclobutyl), -CH2C (O) NH (cyclopropyl), -CH2C (O) NH (oxetanyl), -CH2C (O) NH (tetrahydropyranyl), -CH2CH2S(O)2(morpholinyl) or-CH2CH2S(O)2(phenyl); and R is1、R2、R4、R5M, n and p are as defined in the first or second aspect. Also included are compounds wherein m is 0 and n is 0.
One embodiment provides a compound of formula (I) or a salt thereof, wherein R3Is H, C1-5Alkyl radical, C2-3Fluoroalkyl radical, C1-3Cyanoalkyl, C2-5Hydroxyalkyl, -CH2CH2OCH3、-CH2N(CH3)2、-CH2CH2NH(CH3)、-C＝N(NH2)、-C(O)CH3、-C(O)CH(CH2CH3)2、-C(O)CH2CF3、-C(O)CH2CH2OH、-C(O)CH(CH3)OH、-C(O)CH2CH(CH3)OH、-C(O)CH2C(CH3)2OH、-C(O)CH2CN、-C(O)CH2CH2CN、-C(O)OC(CH3)3、-C(O)CH2OCH3、-C(O)CH2CH2OCH3、-C(O)OCH2CH2NH2、-C(O)OCH2CH2N(CH3)2、-C(O)OCH2CH2N(CH2CH3)2、-C(O)CH2S(O)2CH3、-C(O)CH2CH2S(O)2CH3、-C(O)CH2NHS(O)2CH3、-C(O)NH(CH2C(CH3)3)、-C(O)CH2NH(CH3)、-C(O)CH2NH(CH2CH3)、-C(O)CH2NH(CH2CH2CH3)、-C(O)CH2NH(CH2CH2CH3)、-C(O)CH2NH(CH(CH3)2)、-C(O)CH2NH(CH2CH(CH3)2)、-C(O)CH2NH(C(CH3)3)、-C(O)CH2N(CH3)2、-C(O)CH2N(CH3)(CH2CH3)、-C(O)CH2N(CH3)(CH2CH2CH3)、-C(O)CH2N(CH3)(CH(CH3)2)、-C(O)CH2N(CH3)(CH2CH(CH3)2)、-C(O)CH2N(CH2CH3)2、-C(O)CH2CH2NH(CH3)、-C(O)CH2CH2NH(CH2CH3)、-C(O)CH2CH2NH(CH2CH2CH3)、-C(O)CH2CH2NH(CH(CH3)2)、-C(O)CH2CH2NH(CH2C(CH3)3)、-C(O)CH2CH2N(CH3)2、-C(O)CH2CH2N(CH3)(CH2CH3)、-C(O)CH2CH2N(CH3)(CH2CH2CH3)、-C(O)CH2CH2N(CH3)(CH(CH3)2)、-C(O)CH(CH3)NH(CH3)、-C(O)CH2NH(CH2CN)、-C(O)CH2N(CH3)(CH2CH2CN)、-C(O)CH2NH(CH2C(O)NH2)、-C(O)CH2N(CH3)(CH2C(O)N(CH3)2)、-C(O)CH2CH2NH(CH2C(O)NH2)、-C(O)CH2CH2N(CH3)CH2C(O)N(CH3)2、-C(O)CH2NH(CH2CH2OH)、-C(O)CH2N(CH3)(CH2CH2OH)、-C(O)CH2CH2NH(CH2CH2OH)、-C(O)CH2CH2N(CH3)(CH2CH2OH)、-C(O)CH2NH(CH2CH2F)、-C(O)CH2NH(CH2CF3)、-C(O)CH2CH2NH(CH2CH2F)、-C(O)CH2NH(CH2CH2OCH3)、-C(O)CH2N(CH3)(CH2CH2OCH3)、-C(O)CH2CH2NH(CH2CH2OCH3)、-C(O)CH2CH2N(CH3)(CH2CH2OCH3)、-C(O)CH2N(CH2CH2OCH3)2、-C(O)CH2CH2CH2S(O)2NH2、-CH2C(O)NH2、-CH2C(O)NH(CH3)、-CH2C(O)N(CH3)2、-CH2C(O)NH(CH2CH3)、-CH2C(O)N(CH3)(CH2CH3)、-CH2C(O)N(CH2CH3)2、-CH2C(O)NH(CH2CH2CH3)、-CH2C(O)NH(CH(CH3)2)、-CH(CN)C(O)N(CH3)2、-CH2C(O)NH(CH2CH2CF3)、-CH2C(O)N(CH3)(CH2CH2OH)、-CH2C(O)N(CH3)(CH2CH2OH)、-CH2C(O)N(CH2CH3)(CH2CH2OH)、-CH2C(O)N(CH2CH2CH3)(CH2CH2OH)、-CH2C(O)N(CH3)(CH2CH2CH2OH)、-CH2C(O)NH(CH2C(CH3)2OH)、-CH2C(O)N(CH2CH(CH3)CH2CH3)(CH2CH2OH)、-CH2C(O)NH(CH2CH2CN)、-CH2C(O)N(CH3)(CH2CH2CN)、-CH2C(O)N(CH3)(CH2CH2OCH3)、-CH(CH3)CH2S(O)2(CH2CH2CH2CH3)、-CH2CH2S(O)2NH2、-CH2CH2S(O)2NH(CH3)、-CH2CH2S(O)2N(CH3)2、-CH(CH3)CH2S(O)2N(CH2CH3)2、-CH2CH2NHS(O)2CH3、-CH2CH2N(CH3)S(O)2CH3、-CH2C(O)NH(CH2CH2SCH3)、-C(O)NH(CH2CH2NH2)、-C(O)N(CH3)CH2CH2NH2、-C(O)NH(CH2CH2N(CH3)2)、-C(O)NH(CH2CH2CH2NH2)、-CH2CH2S(O)2CH3、-CH2CH2CH2S(O)2CH3or-CH (CH)3)CH2S(O)2CH3(ii) a And R is1、R2、R4、R5M, n and p are as defined in the first or second aspect. Also included are compounds wherein m is 0 and n is 0.
One embodiment provides a compound of formula (I) or a salt thereof, wherein each R4Independently F, -OH, C1-2Alkyl or-OCH3(ii) a Or two R attached to the same carbon atom4To form ═ O; and R is1、R2、R3、R5M, n and p are defined in the first aspect. In this embodiment include wherein each R is4Independently of each other are F, -CH3or-OCH3The compound of (1). Also included are compounds wherein n is 0.
One embodiment provides a compound of formula (I) or a salt thereof, wherein each R 5Independently of each other is F, Cl, -CN, -CH3、-CF3or-OCH3(ii) a And R is1、R2、R3、R4M, n and p are defined in the first aspect. In this embodiment include wherein each R is5Independently F, -CN, -CH3or-CF3The compound of (1). Also included are compounds wherein m is 0. Also included are compounds wherein m is 0 and n is 1.
One embodiment provides a compound of formula (I) or a salt thereof, wherein m is 2, 3 or 4; two R each attached to a different carbon atom adjacent to the nitrogen atom in the piperidinyl ring4Can form-CH2CH2-a bridge; and R is1、R2、R3、R5M, n and p are defined in the first aspect. The compounds of this embodiment have the structure of formula (Ia):
Figure BDA0001979596660000171
included in this embodiment are compounds wherein R is1is-CH (CH)3)2(ii) a Each R2is-CH3；R3is-CH2CN、-CH2C(O)N(CH3)2or-CH2CH2S(O)2CH3(ii) a m is 2; n is 0; and p is 0, 1 or 2. Also included in this embodiment are compounds selected from the group consisting of:
2- (3- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) -8-azabicyclo [3.2.1] oct-8-yl) acetonitrile (981);
2- (3- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) -8-azabicyclo [3.2.1] oct-8-yl) -N, N-dimethylacetamide (982-carboxylic acid 983); and
6- (3-isopropyl-5- (8- (2- (methylsulfonyl) ethyl) -8-azabicyclo [3.2.1] oct-3-yl) -1H-indol-2-yl) -7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (984-.
One embodiment provides a compound of formula (I) or a salt thereof, wherein R1Is H, Cl, -CN, C1-4Alkyl or C1-2A fluoroalkyl group; each R2Independently F, Cl, -CN, -OH, C1-3Alkyl, -CD3、C1-2Fluoroalkyl radical, C1-2Cyanoalkyl, C1-3Hydroxyalkyl radical, C1-3Aminoalkyl, -O (CH)2)1-2OH、-O(C1-4Alkyl group), C1-2Fluoroalkoxy, - (CH)2)1-4O(C1-3Alkyl), -O (CH)2)1-2OC(O)(C1-3Alkyl), -O (CH)2)1-2NRxRx、-C(O)O(C1-3Alkyl), -C (O) NRyRy、-NRyRy、-NRy(C1-3Fluoroalkyl group), -NRy(C1-4Hydroxyalkyl), -NRxCH2(phenyl), -NRxS(O)2(C3-6Cycloalkyl), -NR-xC(O)(C1-3Alkyl), -NR-x(CH2-cyclopropyl), C3-6Cycloalkyl, morpholinyl, dioxothiomorpholinyl, methylpiperidinyl, methylpiperazinyl, amino-oxadiazolyl, imidazolyl, triazolyl or-C (O) (thiazolyl); r3Comprises the following steps: (a) -L1-a; or (b) H, C1-6Alkyl radical, C1-3Fluoroalkyl radical, C1-3Cyanoalkyl, C1-5Hydroxyalkyl, -C ═ N (NR)xRx)、-(CRxRx)1-2O(C1-2Alkyl), - (CR)xRx)1-4O(CRxRx)1-3O(C1-3Alkyl), -CH2CH(OH)CH2O(C1-3Alkyl), - (CR)xRx)1-3S(C1-3Alkyl), - (CH)2)1-3C(O)OC(CH3)3、-(CRxRx)0- 3NRxRy、-(CRxRx)0-3NRx(C1-4Hydroxyalkyl), -CH2CH(OH)CH2NRxRy、-C(O)(C1-6Alkyl), -C (O) (C)1-4Hydroxyalkyl), -C (O) (C)1-3Fluoroalkyl), -C (O) (C)1-3Chloroalkyl), -C (O) (C)1-3Cyanoalkyl), - (CR)xRx)0-3C(O)OH、-C(O)(CH2)0-2O(C1-4Alkyl), -C (O) (CR)xRx)0-2O(CRxRx)1-2O(C1-3Alkyl), -C (O) (CH)2)0-2O(CH2)1-2HRyRy、-C(O)CRxRxS(O)2(C1-2Alkyl), -C (O) CRxRxNRxS(O)2(C1-2Alkyl), -C (O) CRxRxOC(O)(C1-3Alkyl), -C (O) (CR)xRx)0-2NRyRy、-C(O)(CRxRx)0-2NRx(C1-2Cyanoalkyl), -C (O) (CR)xRx)0-2NRy(C1-6Hydroxyalkyl), -C (O) (CR)xRx)0-2NRx(C1-3Fluoroalkyl), -C (O) (CR)xRx)0-1NRx(C1-5Hydroxy-fluoroalkyl), -C (O) (CR) xRx)0-1NRx((CRxRx)1-2O(C1-2Alkyl)), -C (O) (CRxRx)0-1NRx(CH2)1-2O(C1-3Hydroxyalkyl), -C (O) (CR)xRx)0-1NRx(CH2)1-2NRxC(O)(C1-2Alkyl), -C (O) (CR)xRx)0-2NRx((CRxRx)1-2O(C1-2Alkyl)), -C (O) (CRxRx)0-1NRx(CRxRx)1-3NRxRx、-C(O)CRx(NH2)(CRxRx)1-4NRxRx、-C(O)CRx(NH2)(CRxRx)1- 4NRxC(O)NRxRx、-C(O)(CRxRx)0-3NRx(CH2)0-1C(O)(C1-3Alkyl), -C (O) (CR)xRx)0-1NRx(CH2)0-1C(O)(C1-3Cyanoalkyl), -C (O) (CR)xRx)0-2NRx(CH2)1-2C(O)NRyRy、-C(O)(CRxRx)0-2NRx(CHRy(CH2OH))、-(CRxRx)1-2C(O)NRyRy、-(CRxRx)1-2C(O)NRy(C1-3Fluoroalkyl group), - (CR)xRx)1-2C(O)NRy(C1-4Hydroxyalkyl), - (CR)xRx)1-2C(O)NRx(C1-3Cyanoalkyl), -CH (CN) C (O) NRyRy、-(CRxRx)1-2C(O)NRx(CH2)1-2O(C1-3Alkyl), - (CR)xRx)1-2C(O)NRxCH(C1-4Alkyl) (C1-3Hydroxyalkyl), - (CH)2)1-2C(O)NRx(CH2)1-2C(O)NRxRx、-(CH2)1-2S(O)2NRx(CH2)1-2S(C1-2Alkyl), - (CH)2)1-2C(O)NRx(CH2)1-2S(O)2OH、-(CH2)1-2C(O)NRx(CH2)1-2NRxC(O)(C1-3Alkyl), - (CH)2)1-2C(O)NRx(CH2)1-3NRxRx、-(CH2)1-2C(O)N(CH2CH3)(CH2)1- 3NRxRx、-(CRxRx)1-3S(O)2(C1-4Alkyl), - (CH)2)0-2S(O)2(C1-3Fluoroalkyl group), - (CH)2)1-2S(O)2NRyRy、-C(O)C(O)OH、-C(O)C(O)NRyRyor-C (O) NRy(CRxRx)1-2NRyRy；L1Is a bond, -CRxRx-、-CRxRxC(O)-、-CRxRxC(O)NRx-or-C (O) (CR)xRx)0-2-; a is a ring selected from: azetidinyl, C3-6Cycloalkyl, dioxotetrahydrothiopyranyl, thiadiazinylalkyl dioxide, thiomorpholinyl dioxide, furyl, imidazolyl, isoquinolinyl, morpholinyl, oxazolyl, 2-oxa-6-azaspiro [3.3 ]]Heptyl, oxetanyl, phenyl, piperazinyl, piperidinyl, pyrazinyl, pyrazolyl, pyridinyl, pyrrolidinyl, pyrrolyl, quinolinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrazolyl, thiadiazolyl, thiazolyl and triazolyl, each of which is-L2-RaAnd 0 to 4RbSubstitution; l is2Is a bond or-CRxRx-；RaComprises the following steps: (a) h, -CN, -OH, C1-3Alkyl radical, C1-2Fluoroalkyl radical, C1-3Hydroxyalkyl, - (CH)2)1-2O(C1-3Alkyl), - (CR)xRx)1-3NHC(O)O(C1-4Alkyl), - (CR)xRx)1- 3NH2、-(CRxRx)1-3NRx(C1-4Alkyl), -O (C)1-2Fluoroalkyl), -S (O)2NRxRx、-NHS(O)2(C1-3Alkyl), -NR-xRx、-NRx(C1-4Alkyl), - (CR)xRx)1-2C(O)OH、-C(O)OH、-C(O)(C1-3Alkyl), -C (O) O (C) 1-3Alkyl), -C (O) NRx(C1-2Alkyl), -C (O) N (C)1-3Alkyl radical)2、-C(O)NRxCH2C(O)NRxRxor-C (O) NRxCH2CH2NHC(O)(C1-3Alkyl groups); (b) c3-6Cycloalkyl or-C (O) NH (C)3-6Cycloalkyl), wherein each cycloalkyl is substituted with 0 to 2 substituents independently selected from: -OH, C1-3Alkyl radical, C1-3Hydroxyalkyl radical, C1-3Fluoroalkyl and-C (O) O (C)1-3Alkyl groups); or (c) A1、-CH2A1、-C(O)A1or-C (O) NHA1Wherein A is1Is furyl, imidazolyl, indolyl, isoxazolyl, octahydropyrrolo [3, 4-c ]]Pyrrolyl, oxazolylOxacyclobutyl, phenyl, piperazinyl, piperidinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolyl, tetrahydrofuryl, tetrahydropyranyl, thiadiazolyl, thiazolyl, thienyl or triazolyl, each of which is substituted with 0 to 3 substituents independently selected from: -OH, C1-3Alkyl radical, C1-3Hydroxyalkyl, -C (O) (C)1-2Alkyl), -C (O) O (C)1-3Alkyl), -NR-xRxPhenyl, trifluoromethyl-phenyl, -CH2(bromophenyl) and-CH2CH2(pyrrolidinyl); each R4Independently F, -OH, C1-2Alkyl or-OCH3(ii) a Or two R attached to the same carbon atom4To form ═ O; r5Is F, Cl, -CN, C1-2Alkyl or-OCH3(ii) a Each RbIndependently is-CH3or-CF3(ii) a Each RxIndependently is H or-CH3(ii) a Each RyIndependently is H or C1-5An alkyl group; m is 0, 1 or 2; n is 0 or 1; and p is 0, 1 or 2.
One embodiment provides a compound of formula (I) or a salt thereof, wherein R1is-CH (CH)3)2(ii) a Each R2Independently is-CH3、-OCH3or-CH2OCH3；R3Is H, -CH (CH)3)2、-CH(CH3)2、-CH2CH(CH3)2、-CH2CN、-CH2CH2CN、-CH2CH2CH2CN、-CH2C(CH3)2OH、-C(O)CH3、-C(O)CH(CH2CH3)2、-C(O)CH2OCH3、-C(O)CH2CH2OCH3、-C(O)CH2CH(CH3)OH、-C(O)CH2CN、-C(O)CH2CH2CN、-C(O)CH(CH3)NH(CH3)、-C(O)CH2NH(CH3)、-C(O)CH2N(CH3)2、-C(O)CH2NHCH2CH2CH3、-C(O)CH2NHCH(CH3)2、-C(O)CH2NHC(CH3)3、-C(O)CH2N(CH3)CH(CH3)2、-C(O)CH2NHCH2CH2OCH3、-CH2C(O)NH2、-CH2C(O)NH(CH3)、-CH2C(O)N(CH3)CH2CH3、-CH2C(O)NHCH2CH2CH3、-CH2C(O)NH(CH(CH3)2)、-CH2C(O)N(CH3)2、-CH2C(O)N(CH2CH3)2、-CH2CH2S(O)2CH3、-CH2CH2S(O)2NH2、-CH2C (O) NH (cyclobutyl), -CH2C (O) NH (cyclopropyl), -CH2C (O) NH (methyloxetanyl), -CH2C(O)N(CH3) (cyclopropyl), oxetanyl, tetrahydropyranyl, dioxotetrahydrothiopyranyl, -CH2(oxazolyl), -CH2(pyrazolyl), -CH2(tetrazolyl), -CH2(triazolyl), -CH2(methyltriazolyl), -CH2C (O) (2-oxa-6-azaspiro [3.3 ]]Heptyl), -CH2C (O) (azetidinyl), -CH2C (O) (thiadiazinyl dioxide), -CH2C (O) (thiomorpholinyl sulfate), -CH2C (O) (morpholinyl), -CH2C (O) (methoxyethylpiperazinyl), -CH2C (O) (piperidinyl), -CH2C (O) (hydroxypiperidinyl), -CH2C (O) (pyrrolidinyl), -CH2C (O) (hydroxypyrrolidinyl), -C (O) (azetidinyl), -C (O) (methylcyclopropyl), -C (O) (methyloxetanyl), or-C (O) CH2(morpholinyl); m is 0; n is 0; and p is 0, 1 or 2.
One embodiment provides a compound of formula (I) or a salt thereof, wherein R1Is H, Cl, -CN, C1-4Alkyl radical, C1-2Fluoroalkyl radical, C1-2Hydroxy-fluoroalkyl, C3-6Cycloalkyl, -CH2(C3-6Cycloalkyl), -C (O) O (C)1-2Alkyl) or tetrahydropyranyl; and R is2、R3、R4、R5M, n and p are defined in the first aspect. In that In this embodiment include those wherein R1Is H, Cl, -CN, C1-4Alkyl or C1-2A compound of fluoroalkyl group. Also included in this embodiment are those in which R1is-CH (CH)3)2The compound of (1). Also included are compounds wherein m is 0 and n is 0.
One embodiment provides a compound of formula (I) or a salt thereof, wherein each R2Independently F, Cl, -CN, -OH, C1-3Alkyl radical, C1-2Fluoroalkyl radical, C1-3Hydroxyalkyl radical, C1-3Aminoalkyl, - (CH)2)0-2O(C1-2Alkyl group), C1-3Fluoroalkoxy or C3-6A cycloalkyl group; and R is1、R3、R4、R5M, n and p are defined in the first aspect. In this embodiment include wherein each R is2Independently F, -CN, -OH, C1-2Alkyl or- (CH)2)0-1O(C1-2Alkyl) compounds. Also included in this embodiment are those in which each R is2Independently is-CH3、-OCH3or-CH2OCH3The compound of (1). Also included are compounds wherein m is 0 and n is 0.
One embodiment provides a compound of formula (I) or a salt thereof, wherein each R2Independently F, -CN, -OH, C1-2Alkyl or- (CH)2)0-1O(C1-2Alkyl groups); p is 0, 1 or 2; and R is1、R3、R4、R5M and n are defined in the first aspect. In this embodiment include wherein each R is2Independently is-CH3、-OCH3or-CH2OCH3The compound of (1). Also included are compounds wherein m is 0 and n is 0.
One embodiment provides a compound of formula (I) or a salt thereof, wherein the compound has one of the following structures:
Figure BDA0001979596660000201
In this embodiment include those wherein R1Is H, Cl, -CN、C1-4Alkyl or C1-2A compound of fluoroalkyl group. Also included in this embodiment are those in which R1is-CH (CH)3)2The compound of (1). Also included are compounds wherein m is 0 and n is 0.
One embodiment provides a compound of formula (I) or a salt thereof, wherein R3is-L1-a; and R is1、R2、R4、R5、L1A, m, n and p are defined in the first aspect. Included in this embodiment are compounds wherein L1Is a bond, -CRxRx-、-CRxRxC(O)-、-CRxRxC(O)NRx-or-C (O) (CR)xRx)0-2-; a is a ring selected from: azetidinyl, C3-6Cycloalkyl, dioxotetrahydrothiopyranyl, thiazinoalkyl, thiomorpholinyl, furyl, imidazolyl, isoquinolinyl, morpholinyl, oxazolyl, 2-oxa-6-azaspiro [3.3 ]]Heptyl, oxetanyl, phenyl, piperazinyl, piperidinyl, pyrazinyl, pyrazolyl, pyridinyl, pyrrolidinyl, pyrrolyl, quinolinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrazolyl, thiadiazolyl, thiazolyl and triazolyl, each of which is-L2-RaAnd 0 to 4RbSubstitution; l is2Is a bond or-CRxRx-；RaIs (a) H, -CN, -OH, C1-3Alkyl radical, C1-2Fluoroalkyl radical, C1-3Hydroxyalkyl, - (CH)2)1-2O(C1-3Alkyl), - (CR)xRx)1-3NHC(O)O(C1-4Alkyl), - (CR)xRx)1- 3NH2、-(CRxRx)1-3NRx(C1-4Alkyl), -O (C)1-2Fluoroalkyl), -S (O) 2NRxRx、-NHS(O)2(C1-3Alkyl), -NR-xRx、-NRx(C1-4Alkyl), - (CR)xRx)1-2C(O)OH、-C(O)OH、-C(O)(C1-3Alkyl), -C (O) O (C)1-3Alkyl), -C (O) NRx(C1-2Alkyl), -C (O) N (C)1-3Alkyl radical)2、-C(O)NRxCH2C(O)NRxRxor-C (O) NRxCH2CH2NHC(O)(C1-3Alkyl groups); (b) c3-6Cycloalkyl or-C (O) NH (C)3-6Cycloalkyl), wherein each cycloalkyl is substituted with 0 to 2 substituents independently selected from: -OH, C1-3Alkyl radical, C1-3Hydroxyalkyl radical, C1-3Fluoroalkyl and-C (O) O (C)1-3Alkyl groups); or (c) A1、-CH2A1、-C(O)A1or-C (O) NHA1Wherein A is1Is furyl, imidazolyl, indolyl, isoxazolyl, octahydropyrrolo [3, 4-c ]]Pyrrolyl, oxazolyl, oxetanyl, phenyl, piperazinyl, piperidinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolyl, tetrahydrofuryl, tetrahydropyranyl, thiadiazolyl, thiazolyl, thienyl or triazolyl, each of which is substituted with 0 to 3 substituents independently selected from: -OH, C1-3Alkyl radical, C1-3Hydroxyalkyl, -C (O) (C)1-2Alkyl), -C (O) O (C)1-3Alkyl), -NR-xRxPhenyl, trifluoromethyl-phenyl, -CH2(bromophenyl) and-CH2CH2(pyrrolidinyl); each RbIndependently is-CH3or-CF3(ii) a And each RxIndependently is H or-CH3. Included in this embodiment are compounds wherein R is3is-CH2C (O) NH (cyclobutyl), -CH2C (O) NH (cyclopropyl), -CH2C (O) NH (methyloxetanyl), -CH 2C(O)N(CH3) (cyclopropyl), oxetanyl, tetrahydropyranyl, dioxotetrahydrothiopyranyl, -CH2(oxazolyl), -CH2(pyrazolyl), -CH2(tetrazolyl), -CH2(triazolyl), -CH2(methyltriazolyl), -CH2C (O) (2-oxa-6-azaspiro [3.3 ]]Heptyl), -CH2C (O) (azetidinyl), -CH2C (O) (thiadiazinyl dioxide), -CH2C (O) (thiomorpholinyl sulfate), -CH2C (O) (morpholinyl), -CH2C (O) (methoxyethylpiperazinyl),-CH2C (O) (piperidinyl), -CH2C (O) (hydroxypiperidinyl), -CH2C (O) (pyrrolidinyl), -CH2C (O) (hydroxypyrrolidinyl), -C (O) (azetidinyl), -C (O) (methylcyclopropyl), -C (O) (methyloxetanyl), or-C (O) CH2(morpholinyl). Also included are compounds wherein m is 0 and n is 0.
One embodiment provides a compound of formula (I) or a salt thereof, wherein R3Is H, C1-6Alkyl radical, C1-3Cyanoalkyl, C1-4Hydroxyalkyl, - (CR)xRx)1-4O(C1-3Alkyl), - (CR)xRx)1-4O(CRxRx)1-3O(C1-3Alkyl), -CH2CH(OH)CH2O(C1-3Alkyl), - (CR)xRx)1-3S(C1-3Alkyl), - (CH)2)1-3C(O)OC(CH3)3、-(CRxRx)0-3NRxRy、-(CRxRx)0-3NRx(C1-4Hydroxyalkyl), -CH2CH(OH)CH2NRxRy、-C(O)(C1-6Alkyl), -C (O) (C)1-3Hydroxyalkyl), -C (O) (C)1-3Fluoroalkyl), -C (O) (C)1-3Chloroalkyl), -C (O) (C)1-3Cyanoalkyl), - (CR)xRx)0-3C(O)OH、-C(O)(CH2)1-2O(C1-2Alkyl), -C (O) (CR)xRx)0-2O(CRxRx)1-2O(C1-3Alkyl), -C (O) CRxRxS(O)2(C1-3Alkyl), -C (O) CRxRxNRxS(O)2(C1-3Alkyl), -C (O) CRxRxOC(O)(C1-3Alkyl), -C (O) (CR)xRx)0-3NRyRy、-C(O)(CRxRx)0-1NRx(C1-3Cyanoalkyl), -C (O) (CR) xRx)0-2NRy(C1-6Hydroxyalkyl), -C (O) (CR)xRx)0-1NRx(C1-3Fluoroalkyl), -C (O) (CR)xRx)0-1NRx(C1-5Hydroxy-fluoroalkyl), -C (O) (CR)xRx)0-1NRx(CH2)1-2O(C1-3Hydroxyalkyl), -C (O) (CR)xRx)0-1NRx(CH2)1-2NRxC(O)(C1-2Alkyl), -C (O) (CR)xRx)0-1NRx((CRxRx)1-2O(C1-2Alkyl)), -C (O) CRx(NH2)(CRxRx)1-4NRxRx、-C(O)CRx(NH2)(CRxRx)1-4NRxC(O)NRxRx、-C(O)(CRxRx)0-3NRx(CH2)0-1C(O)(C1-3Alkyl), -C (O) (CR)xRx)0-1NRx(CH2)0-1C(O)(C1-3Cyanoalkyl), -C (O) (CR)xRx)0-1NRx(CH2)1-2C(O)NRyRy、-C(O)(CRxRx)0-1NRx(CHRy(CH2OH))、-(CRxRx)1-2C(O)NRyRy、-(CRxRx)1-2C(O)NRy(C1-3Fluoroalkyl group), - (CR)xRx)1-2C(O)NRy(C1-4Hydroxyalkyl), - (CR)xRx)1-2C(O)NRy(C1-3Cyanoalkyl), - (CR)xRx)1- 2C(O)NRx(CH2)1-2O(C1-3Alkyl), - (CR)xRx)1-2C(O)NRxCH(C1-4Alkyl) (C1-3Hydroxyalkyl), - (CH)2)1-2C(O)NRx(CH2)1-2C(O)NRxRx、-(CH2)1-2C(O)NRx(CH2)1-2S(O)2OH、-(CH2)1-2C(O)NRx(CH2)1-2NRxC(O)(C1-3Alkyl), - (CH)2)1-2C(O)NRx(CH2)1-3NRxRx、-(CH2)1-2C(O)N(CH2CH3)(CH2)1-3NRxRx、-(CH2)1-2S(O)2(C1-4Alkyl), - (CH)2)0-2S(O)2(C1-3Fluoroalkyl group), - (CH)2)1-2S(O)2NRxRx、-C(O)C(O)OH、-C(O)C(O)NRyRyor-C (O) NRy(CRxRx)1-2NRyRy(ii) a And R is1、R2、R4、R5、Rx、RyM, n and p are defined in the first aspect. Included in this embodiment are compounds wherein R is3Is H, -CH (CH)3)2、-CH(CH3)2、-CH2CH(CH3)2、-CH2CN、-CH2CH2CN、-CH2CH2CH2CN、-CH2C(CH3)2OH、-C(O)CH3、-C(O)CH(CH2CH3)2、-C(O)CH2OCH3、-C(O)CH2CH2OCH3、-C(O)CH2CH(CH3)OH、-C(O)CH2CN、-C(O)CH2CH2CN、-C(O)CH(CH3)NH(CH3)、-C(O)CH2NH(CH3)、-C(O)CH2N(CH3)2、-C(O)CH2NHCH2CH2CH3、-C(O)CH2NHCH(CH3)2、-C(O)CH2NHC(CH3)3、-C(O)CH2N(CH3)CH(CH3)2、-C(O)CH2NHCH2CH2OCH3、-CH2C(O)NH2、-CH2C(O)NH(CH3)、-CH2C(O)N(CH3)CH2CH3、-CH2C(O)NHCH2CH2CH3、-CH2C(O)NH(CH(CH3)2)、-CH2C(O)N(CH3)2、-CH2C(O)N(CH2CH3)2、-CH2CH2S(O)2CH3or-CH2CH2S(O)2NH2. Also included are compounds wherein m is 0 and n is 0.
One embodiment provides a compound of formula (I) or a salt thereof, wherein R3Is H, -CH (CH)3)2、-CH(CH3)2、-CH2CH(CH3)2、-CH2CN、-CH2CH2CN、-CH2CH2CH2CN、-CH2C(CH3)2OH、-C(O)CH3、-C(O)CH(CH2CH3)2、-C(O)CH2OCH3、-C(O)CH2CH2OCH3、-C(O)CH2CH(CH3)OH、-C(O)CH2CN、-C(O)CH2CH2CN、-C(O)CH(CH3)NH(CH3)、-C(O)CH2NH(CH3)、-C(O)CH2N(CH3)2、-C(O)CH2NHCH2CH2CH3、-C(O)CH2NHCH(CH3)2、-C(O)CH2NHC(CH3)3、-C(O)CH2N(CH3)CH(CH3)2、-C(O)CH2NHCH2CH2OCH3、-CH2C(O)NH2、-CH2C(O)NH(CH3)、-CH2C(O)N(CH3)CH2CH3、-CH2C(O)NHCH2CH2CH3、-CH2C(O)NH(CH(CH3)2)、-CH2C(O)N(CH3)2、-CH2C(O)N(CH2CH3)2、-CH2CH2S(O)2CH3、-CH2CH2S(O)2NH2、-CH2C (O) NH (cyclobutyl), -CH2C (O) NH (cyclopropyl), -CH2C (O) NH (methyloxetanyl), -CH2C(O)N(CH3) (cyclopropyl), oxetanyl, tetrahydropyranyl, dioxotetrahydrothiopyranyl, -CH2(oxazolyl), -CH2(pyrazolyl), -CH2(tetrazolyl), -CH2(triazolyl), -CH2(methyltriazolyl), -CH2C (O) (2-oxa-6-azaspiro [3.3 ]]Heptyl), -CH2C (O) (azetidinyl), -CH2C (O) (thiadiazinyl dioxide), -CH2C (O) (thiomorpholinyl sulfate), -CH2C (O) (morpholinyl), -CH2C (O) (methoxyethylpiperazinyl), -CH 2C (O) (piperidinyl), -CH2C (O) (hydroxypiperidinyl), -CH2C (O) (pyrrolidinyl), -CH2C (O) (hydroxypyrrolidinyl), -C (O) (azetidinyl), -C (O) (methylcyclopropyl), -C (O) (methyloxetanyl), or-C (O) CH2(morpholinyl); and R is1、R2、R4、R5M, n and p are defined in the first aspect. Included in this embodiment are compounds wherein each R is2Independently F, -CN, -OH, C1-2Alkyl or- (CH)2)0-1O(C1-2Alkyl groups); p is 0, 1 or 2. In this embodiment include wherein each R is2Independently is-CH3、-OCH3or-CH2OCH3The compound of (1). Also included are compounds wherein m is 0 and n is 0.
One embodiment provides a compound of formula (I) or a salt thereof, wherein m is 0, 1 or 2; and R is1、R2、R3、R4、R5N and p are defined in the first aspect. Included in this embodiment are compounds wherein m is 0 or 1. Also included in this embodiment are compounds wherein m is 0. Also included are compounds wherein m is 0 and n is 0.
One embodiment provides a compound of formula (I) or a salt thereof, wherein n is 0 or 1; and R is1、R2、R3、R4、R5M and p are defined in the first aspect. Included in this embodiment are those in which n is 0A compound (I) is provided. Also included are compounds wherein m is 0. Also included are compounds wherein m is 0 and n is 0.
One embodiment provides a compound of formula (I) or a salt thereof, wherein m is 0, 1 or 2; n is 0 or 1; and p is 0, 1 or 2; and R is 1、R2、R3、R4And R5As defined in the first aspect. Included in this embodiment are compounds wherein m is 0 or 1; n is 0; and p is 0, 1 or 2. Also included are compounds wherein m is 0; n is 0; and p is 0, 1 or 2.
One embodiment provides a compound of formula (I) or a salt thereof, wherein the compound has the structure of formula (I-1):
Figure BDA0001979596660000241
and R is1、R3、R4、R5M and n are defined in the first or second aspect. In this embodiment include those wherein R1is-CH2CH3or-CH (CH)3)2The compound of (1). Included in this embodiment are compounds wherein R is3Is H, -CH3、-CH(CH3)2、-CH2CHF2、-CH2CH2OH、-CH2C(O)NH2、-CH2C(O)NH(CH3)、-CH2C(O)NH(CH3)、-CH2C(O)N(CH3)2、-CH2C(CH3)2OH、-C(O)CH2S(O)2CH3、-C(O)CH2NH(CH3)、-C(O)CH2N(CH3)2、-C(O)CH2CH(CH3) OH or-L1-A；L1is-CH2-, -C (O) -or-C (O) CH2CH(CH3) -; and A is isoxazolyl, oxazolyl, oxetanyl, pyrazolyl, pyrimidinyl, pyrrolidinonyl, tetrahydrofuryl, tetrahydropyranyl, thiazolyl or triazolyl, each of which is-L2-RaAnd 0 to 2RbSubstitution; l is2Is a bond;Rais H, C1-3Alkyl, -OCH3or-CH2(cyclopropyl); and each Rbis-CH3. Also included in this embodiment are compounds wherein R is1is-CH (CH)3)2(ii) a m is 0; and n is 0.
One embodiment provides a compound of formula (I) or a salt thereof, wherein the compound is:
6- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridine (1);
1- (4- (2- ([1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -2- (methylamino) ethan-1-one (47);
1- (4- (2- ([1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -2- (dimethylamino) ethan-1-one (51);
(S) -1- (4- (2- ([1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -3-hydroxybutan-1-one (53);
6- (3-ethyl-5- (piperidin-4-yl) -1H-indol-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridine (121);
2- (4- (2- ([1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -N, N-dimethylacetamide (164);
2- (4- (2- ([1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -N-methylacetamide (240);
1- (4- (2- ([1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -2-methylpropan-2-ol (241);
2- (4- (2- ([1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -N-methylacetamide (242);
6- (3-isopropyl-5- (1-methylpiperidin-4-yl) -1H-indol-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridine (350);
6- (3-isopropyl-5- (1- (tetrahydro-2H-pyran-4-yl) piperidin-4-yl) -1H-indol-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridine (351);
6- (3-isopropyl-5- (1- (oxetan-3-yl) piperidin-4-yl) -1H-indol-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridine (352);
6- (3-isopropyl-5- (1- ((1-methyl-1H-1, 2, 4-triazol-3-yl) methyl) piperidin-4-yl) -1H-indol-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridine (353);
6- (3-isopropyl-5- (1- (tetrahydro-2H-pyran-3-yl) piperidin-4-yl) -1H-indol-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridine (354);
6- (3-isopropyl-5- (1- (tetrahydrofuran-3-yl) piperidin-4-yl) -1H-indol-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridine (355);
2- (4- (2- ([1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) ethan-1-ol (356);
6- (3-isopropyl-5- (1- (oxetan-3-ylmethyl) piperidin-4-yl) -1H-indol-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridine (358);
6- (3-isopropyl-5- (1- ((2-methoxypyrimidin-5-yl) methyl) piperidin-4-yl) -1H-indol-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridine (359);
2- (4- (2- ([1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) acetamide (360);
3- ((4- (2- ([1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) methyl) -5-methylisoxazole (361);
4- ((4- (2- ([1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) methyl) -2-isopropylthiazole (362);
6- (3-isopropyl-5- (1- ((1-propyl-1H-pyrazol-4-yl) methyl) piperidin-4-yl) -1H-indol-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridine (363);
6- (5- (1- ((3, 5-dimethyl-1H-pyrazol-4-yl) methyl) piperidin-4-yl) -3-isopropyl-1H-indol-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridine (364);
6- (5- (1- ((1H-1, 2, 3-triazol-4-yl) methyl) piperidin-4-yl) -3-isopropyl-1H-indol-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridine (365);
6- (5- (1- ((1- (cyclopropylmethyl) -1H-pyrazol-3-yl) methyl) piperidin-4-yl) -3-isopropyl-1H-indol-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridine (366);
6- (3-isopropyl-5- (1- ((1-methyl-1H-1, 2, 3-triazol-4-yl) methyl) piperidin-4-yl) -1H-indol-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridine (367);
6- (3-isopropyl-5- (1- ((5-methoxy-1, 3-dimethyl-1H-pyrazol-4-yl) methyl) piperidin-4-yl) -1H-indol-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridine (368);
5- ((4- (2- ([1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) methyl) -2, 4-dimethylthiazole (369);
4- ((4- (2- ([1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) methyl) -3, 5-dimethylisoxazole (370);
6- (5- (1- ((1, 3-dimethyl-1H-pyrazol-4-yl) methyl) piperidin-4-yl) -3-isopropyl-1H-indol-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridine (371);
4- ((4- (2- ([1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) methyl) -2, 5-dimethyloxazole (372);
6- (5- (1- ((1, 3-dimethyl-1H-pyrazol-5-yl) methyl) piperidin-4-yl) -3-isopropyl-1H-indol-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridine (373);
2- ((4- (2- ([1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) methyl) thiazole (374);
6- (3-isopropyl-5- (1- ((1-isopropyl-1H-pyrazol-4-yl) methyl) piperidin-4-yl) -1H-indol-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridine (375);
6- (3-isopropyl-5- (1- ((1-methyl-1H-pyrazol-4-yl) methyl) piperidin-4-yl) -1H-indol-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridine (376);
5- ((4- (2- ([1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) methyl) thiazole (377);
4- ((4- (2- ([1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) methyl) -2-methyloxazole (378);
6- (5- (1- ((1H-pyrazol-5-yl) methyl) piperidin-4-yl) -3-isopropyl-1H-indol-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridine (379);
6- (3-isopropyl-5- (1- ((3-methyl-1H-pyrazol-4-yl) methyl) piperidin-4-yl) -1H-indol-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridine (380);
6- (3-isopropyl-5- (1- ((1-methyl-1H-pyrazol-3-yl) methyl) piperidin-4-yl) -1H-indol-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridine (381);
6- (5- (1- ((1-ethyl-1H-pyrazol-3-yl) methyl) piperidin-4-yl) -3-isopropyl-1H-indol-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridine (382);
2- ((4- (2- ([1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) methyl) -5-methylthiazole (383);
4- ((4- (2- ([1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) methyl) oxazole (384);
6- (3-isopropyl-5- (1-isopropylpiperidin-4-yl) -1H-indol-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridine (536);
4- (4- (2- ([1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidine-1-carbonyl) -1-methylpyrrolidin-2-one (601);
1- (4- (2- ([1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -2- (methylsulfonyl) ethan-1-one (619); or
1- (4- (2- ([1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -3- (oxetan-3-yl) butan-1-one (713).
One embodiment provides a compound of formula (I) or a salt thereof, wherein the compound has the structure of formula (I-2):
Figure BDA0001979596660000281
and R is1、R3、R4、R5M and n are defined in the first or second aspect. In this embodiment include those wherein R1is-CH (CH)3)2The compound of (1). Included in this embodiment are compounds wherein R is3Is H, C1-3Cyanoalkyl, -CH2C(CH3)2OH、-CH2C(O)NH(CH3)、-CH2C(O)N(CH3)2、-CH2C(O)NH(CH2CH3)、-CH2C(O)NH(CH(CH3)2)、-CH2C(O)N(CH3)(CH2CH3)、-CH2C(O)N(CH2CH3)2、-CH2C(O)N(CH3)(CH2CH2OH)、-CH2CH2S(O)2CH3、-CH(CH3)CH2S(O)2CH3、-CH2CH2S(O)2NH2、-CH2CH2S(O)2NH(CH3)、-CH2CH2S(O)2N(CH3)2、-CH2CH2NHS(O)2CH3、-C(O)CH2CN or-L1-A；L1is-CH2-、-CH2C(O)-、-CH2C (O) NH-or-C (O) CH2CH2-; and A is cyclopropyl, dioxotetrahydrothienyl, dioxotetrahydrothiopyranyl, isoxazolyl, morpholinyl, oxadiazolyl, oxazolyl, oxetanyl, piperidinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolidinyl, tetrahydropyranyl, thiazolyl or triazolyl, each of which is substituted by-L2-RaAnd 0 to 1R bSubstitution; l is2Is a bond; raIs H, -CH3-CN or-OCH3(ii) a And R isbis-OCH3. Also included in this embodiment are compounds wherein R is1is-CH (CH)3)2(ii) a m is 0; and n is 0.
One embodiment provides a compound of formula (I) or a salt thereof, wherein the compound is:
6- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) -7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (3);
3- (4- (3-isopropyl-2- (7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -3-oxopropanenitrile (49);
2- (4- (3-isopropyl-2- (7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) ethane-1-sulfonamide (180);
2- (4- (3-isopropyl-2- (7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) acetonitrile (181);
1- (4- (3-isopropyl-2- (7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -2-methylpropan-2-ol (182);
2- (4- (3-isopropyl-2- (7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) ethane-1-sulfonamide (183);
2- (4- (3-isopropyl-2- (7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -N-methylethane-1-sulfonamide (184);
2- (4- (3-isopropyl-2- (7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -N, N-dimethylethane-1-sulfonamide (185);
1- ((4- (3-isopropyl-2- (7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) methyl) cyclopropane-1-carbonitrile (186);
1- ((4- (3-isopropyl-2- (7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) methyl) cyclopropane-1-carbonitrile (187);
3- (4- (3-isopropyl-2- (7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) propionitrile (188);
n- (2- (4- (3-isopropyl-2- (7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) ethyl) methanesulfonamide (189);
2- (4- (3-isopropyl-2- (7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -N-methylacetamide (190);
2- (4- (3-isopropyl-2- (7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -N, N-dimethylacetamide (191);
6- (3-isopropyl-5- (1- (oxetan-3-yl) piperidin-4-yl) -1H-indol-2-yl) -7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (441);
6- (3-isopropyl-5- (1- ((2-methoxypyrimidin-5-yl) methyl) piperidin-4-yl) -1H-indol-2-yl) -7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (442);
6- (3-isopropyl-5- (1- (tetrahydro-2H-pyran-4-yl) piperidin-4-yl) -1H-indol-2-yl) -7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (443);
6- (3-isopropyl-5- (1- ((1-methyl-1H-pyrazol-5-yl) methyl) piperidin-4-yl) -1H-indol-2-yl) -7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (444);
6- (3-isopropyl-5- (1- ((1-methyl-1H-pyrazol-3-yl) methyl) piperidin-4-yl) -1H-indol-2-yl) -7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (445);
2- ((4- (3-isopropyl-2- (7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) methyl) oxazole (446);
6- (3-isopropyl-5- (1- ((4-methyl-4H-1, 2, 4-triazol-3-yl) methyl) piperidin-4-yl) -1H-indol-2-yl) -7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (447);
6- (5- (1- ((1H-pyrazol-5-yl) methyl) piperidin-4-yl) -3-isopropyl-1H-indol-2-yl) -7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (448);
6- (3-isopropyl-5- (1- ((1-methyl-1H-1, 2, 3-triazol-4-yl) methyl) piperidin-4-yl) -1H-indol-2-yl) -7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (449);
5- ((4- (3-isopropyl-2- (7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) methyl) thiazole (450);
6- (5- (1- ((1H-1, 2, 3-triazol-5-yl) methyl) piperidin-4-yl) -3-isopropyl-1H-indol-2-yl) -7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (451);
6- (3-isopropyl-5- (1- (pyrimidin-5-ylmethyl) piperidin-4-yl) -1H-indol-2-yl) -7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (452);
3- ((4- (3-isopropyl-2- (7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) methyl) -5-methylisoxazole (453);
6- (3-isopropyl-5- (1- (pyrimidin-2-ylmethyl) piperidin-4-yl) -1H-indol-2-yl) -7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (454);
4- (4- (3-isopropyl-2- (7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) tetrahydro-2H-thiopyran 1, 1-dioxide (455);
6- (5- (1- ((4, 6-dimethoxypyrimidin-2-yl) methyl) piperidin-4-yl) -3-isopropyl-1H-indol-2-yl) -7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (456);
6- (3-isopropyl-5- (1- ((1-methyl-1H-1, 2, 4-triazol-3-yl) methyl) piperidin-4-yl) -1H-indol-2-yl) -7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (457);
2- ((4- (3-isopropyl-2- (7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) methyl) -1, 3, 4-oxadiazole (458);
6- (5- (1- ((1H-1, 2, 4-triazol-5-yl) methyl) piperidin-4-yl) -3-isopropyl-1H-indol-2-yl) -7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (459);
3- (4- (3-isopropyl-2- (7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) tetrahydrothiophene 1, 1-dioxide (460);
6- (3-isopropyl-5- (1- (pyridazin-3-ylmethyl) piperidin-4-yl) -1H-indol-2-yl) -7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine ((461);
3- (4- (3-isopropyl-2- (7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) butyronitrile (462);
6- (3-isopropyl-5- (1- ((2-methylpyrimidin-5-yl) methyl) piperidin-4-yl) -1H-indol-2-yl) -7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (463);
6- (3-isopropyl-5- (1- (1- (methylsulfonyl) propan-2-yl) piperidin-4-yl) -1H-indol-2-yl) -7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (464);
6- (3-isopropyl-5- (1- ((2-methylpyrimidin-4-yl) methyl) piperidin-4-yl) -1H-indol-2-yl) -7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (465);
6- (3-isopropyl-5- (1- ((5-methylpyrazin-2-yl) methyl) piperidin-4-yl) -1H-indol-2-yl) -7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (466);
6- (3-isopropyl-5- (1- (pyrazin-2-ylmethyl) piperidin-4-yl) -1H-indol-2-yl) -7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (467);
2- (4- (3-isopropyl-2- (7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -1- (pyrrolidin-1-yl) ethan-1-one (802);
n-isopropyl-2- (4- (3-isopropyl-2- (7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) acetamide (803);
n-ethyl-2- (4- (3-isopropyl-2- (7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -N-methylacetamide (804);
2- (4- (3-isopropyl-2- (7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -1- (piperidin-1-yl) ethan-1-one (805);
n-cyclopropyl-2- (4- (3-isopropyl-2- (7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) acetamide (806);
n-ethyl-2- (4- (3-isopropyl-2- (7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) acetamide (807);
N, N-diethyl-2- (4- (3-isopropyl-2- (7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) acetamide (808);
2- (4- (3-isopropyl-2- (7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -1-morpholinoethan-1-one (809);
n- (2-hydroxyethyl) -2- (4- (3-isopropyl-2- (7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -N-methylacetamide (810); or
1- (4- (3-isopropyl-2- (7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -3-morpholinopropan-1-one (885).
One embodiment provides a compound of formula (I) or a salt thereof, wherein the compound has the structure of formula (I-3):
Figure BDA0001979596660000321
R2is-CH3or-CD3(ii) a And R is1、R3、R4、R5M and n are defined in the first or second aspect. In this embodiment include those wherein R1is-CH2CH3、-CH(CH3)2or-CH2CHF2The compound of (1). Included in this embodiment are compounds wherein R is3Is H, C3-5Alkyl radical, C2-3Fluoroalkyl radical, C2-5Hydroxyalkyl radical, C1-3Cyanoalkyl, -CH2C(CH3)2OH、-CH2CH2OCH3、-CH2C(O)NH2、-CH2C(O)NH(CH3)、-CH2C(O)NH(CH2CH2CH3)、-CH2C(O)NH(CH(CH3)2)、-CH2C(O)N(CH3)2、-CH2C(O)N(CH3)CH2CH3、-CH2C(O)N(CH2CH3)2、-CH(CN)C(O)N(CH3)2、-CH2C(O)N(CH3)(CH2CH2OH)、-CH2C(O)N(CH2CH3)(CH2CH2OH)、-CH2C(O)N(CH2CH2CH3)(CH2CH2OH)、-CH2C(O)N(CH3)(CH2CH2CH2OH)、-CH2C(O)N(CH3)(CH2C(CH3)2OH)、-CH2C(O)N(CH2CH2OH)(CH2CH(CH3)CH2CH3)、-CH2C(O)NH(CH2CH2SCH3)、-CH2CH2S(O)2CH3、-CH2CH2CH2S(O)2CH3、-CH(CH3)CH2S(O)2CH3、-CH(CH3)CH2S(O)2(CH2CH2CH2CH3)、-CH2CH2S(O)2NH2、-CH2CH2S(O)2NH(CH3)、-CH2CH2S(O)2N(CH3)2、-CH(CH3)CH2S(O)2N(CH2CH3)2、-CH2CH2NHS(O)2CH3、-C＝N(NH2)、-C(O)CH3、-C(O)CH(CH2CH3)2、-C(O)CH2CH2CN、-C(O)CH2CH(CH3)OH、-C(O)CH2OCH3、-C(O)CH2CH2OCH3、-C(O)CH2NH(CH3)、-C(O)CH2NH(CH2CH2CH3)、-C(O)CH2NHCH(CH3)2、-C(O)CH2NHC(CH3)3、-C(O)CH2N(CH3)2、-C(O)CH(CH3)NH(CH3)、-C(O)CH2N(CH3)CH(CH3)2、-C(O)CH2N(CH3)(CH2CH2OH)、-C(O)CH2NH(CH2CH2OCH3)、-C(O)CH2S(O)2CH3、-C(O)CH2CH2S(O)2CH3、-C(O)CH2NHS(O)2CH3or-L1-A；L1is-CH2-、-CH2C(O)-、-CH2C(O)N(CH2CH2OH)-、-CH2C(O)N(CH3)-、-CH2C(O)N(CH3)-、-CH2C(O)N(CH3)CH2CH2-、-CH2C(O)NH-、-CH2CH2S(O)2-、-C(O)-、-C(O)CH2-、-C(O)CH2CH2-、-C(O)CH2CH2N(CH2CH2OH)-、-C(O)CH2N(CH2CH2OH)-、-C(O)CH2NH-、-CH(CH3) -or-CH (CH)3)CH2S(O)2-; and A is 2-oxa-6-azaspiro [3.3]Heptyl, azetidinyl, C3-6Cycloalkyl, thiadiazinyl dioxide, thiazolidinyl dioxide, thiomorpholinyl dioxide, dioxotetrahydrothienyl, dioxotetrahydrothiopyranyl, dioxothiomorpholinyl, imidazolyl, isoxazolyl, morpholinyl, oxa-azaspiro [3.3 ]Heptyl, oxadiazolyl, oxazolyl, oxetanyl, phenyl, piperazinyl, piperidinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolidinonyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrazolyl, thiadiazolyl, thiazolyl or triazolyl, each of which is substituted with-L2-RaAnd 0 to 2RbSubstitution; l is2Is a bond; raIs H, F, -CH3、-CN、-OH、-OCH3、-CH2OH、-CH2CH2OH、-CH2CH2OCH3、-C(O)CH3、-C(O)OCH2CH3、-C(O)OC(CH3)3、-NHC(O)OC(CH3)3、-S(O)2CH3Cyclopropyl or pyrazinyl; and each RbIndependently F, -OH, -CH3or-OCH3. Also included in this embodiment are compounds wherein R is1is-CH (CH)3)2(ii) a m is 0; and n is 0. Also included in this embodiment are those wherein R2is-CH3The compound of (1).
One embodiment provides a compound of formula (I) or a salt thereof, wherein the compound is:
6- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) -8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine hydrochloride (2);
2- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -N-methylacetamide (7);
2- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) acetonitrile (8);
3- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) propionitrile (9);
6- (5- (1-butylpiperidin-4-yl) -3-isopropyl-1H-indol-2-yl) -8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (10);
2- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) acetamide (11);
1- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -2-methylpropan-2-ol (12);
6- (3-isopropyl-5- (1- (oxetan-3-yl) piperidin-4-yl) -1H-indol-2-yl) -8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (26);
6- (3-isopropyl-5- (1-isopropylpiperidin-4-yl) -1H-indol-2-yl) -8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (27);
6- (3-isopropyl-5- (1-propylpiperidin-4-yl) -1H-indol-2-yl) -8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (28);
6- (5- (1-isobutylpiperidin-4-yl) -3-isopropyl-1H-indol-2-yl) -8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (29);
6- (5- (1- ((1H-pyrazol-5-yl) methyl) piperidin-4-yl) -3-isopropyl-1H-indol-2-yl) -8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (30);
4- ((4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) methyl) oxazole (31);
6- (5- (1- ((1H-1, 2, 3-triazol-4-yl) methyl) piperidin-4-yl) -3-isopropyl-1H-indol-2-yl) -8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (32);
6- (5- (1- ((4H-1, 2, 4-triazol-3-yl) methyl) piperidin-4-yl) -3-isopropyl-1H-indol-2-yl) -8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (33);
6- (5- (1- ((1H-tetrazol-5-yl) methyl) piperidin-4-yl) -3-isopropyl-1H-indol-2-yl) -8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (34);
6- (3-isopropyl-5- (1- (tetrahydro-2H-pyran-4-yl) piperidin-4-yl) -1H-indol-2-yl) -8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (35);
2- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -N, N-dimethylacetamide (36);
4- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) tetrahydro-2H-thiopyran 1, 1-dioxide (37);
2- (dimethylamino) -1- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) ethan-1-one (46);
1- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) ethan-1-one (48);
1- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -2- (methylamino) ethan-1-one (50);
1- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -2-methoxyethan-1-one (52);
4- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -4-oxobutanenitrile (54);
(4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) (1-methylcyclopropyl) methanone (55);
(S) -azetidin-2-yl (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) methanone (56);
2- (dimethylamino) -1- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) ethan-1-one (57);
(S) -1- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -2- (methylamino) propan-1-one (58);
(R) -1- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -2- (methylamino) propan-1-one (59);
(S) -3-hydroxy-1- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) butan-1-one (60);
1- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -3-methoxypropan-1-one (61);
(4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) (3-methyloxetan-3-yl) methanone (64);
2-ethyl-1- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) butan-1-one (65);
1- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -2-morpholinoethan-1-one (68);
2- (tert-butylamino) -1- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) ethan-1-one (69);
1- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -2- (isopropylamino) ethan-1-one (70);
1- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -2- ((2-methoxyethyl) amino) ethan-1-one (71);
1- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -2- (propylamino) ethan-1-one (72);
2- (isopropyl (methyl) amino) -1- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) ethan-1-one (73);
1- (1, 1-thiomorpholino) -2- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) ethan-1-one (74);
n-cyclopropyl-2- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) acetamide (75);
n-ethyl-2- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -N-methylacetamide (76);
(S) -1- (3-hydroxypiperidin-1-yl) -2- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) ethan-1-one (77);
n-cyclobutyl-2- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) acetamide (78);
2- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -1- (2-oxa-6-azaspiro [3.3] hept-6-yl) ethan-1-one (79);
N, N-diethyl-2- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) acetamide (80);
2- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -n-propylacetamide (81);
(R) -1- (3-hydroxypiperidin-1-yl) -2- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) ethan-1-one (82);
(S) -1- (3-hydroxypyrrolidin-1-yl) -2- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) ethan-1-one (83);
(R) -1- (3-hydroxypyrrolidin-1-yl) -2- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) ethan-1-one (84);
2- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -1- (4- (2-methoxyethyl) piperazin-1-yl) ethan-1-one (85);
1- (azetidin-1-yl) -2- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) ethan-1-one (86);
n-isopropyl-2- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) acetamide (87);
2- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -1-morpholinoethan-1-one (88);
2- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -1- (piperidin-1-yl) ethan-1-one (89);
2- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -1- (pyrrolidin-1-yl) ethan-1-one (90);
1- (1, 1-thiomorpholino) -2- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) ethan-1-one (91);
2- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -N- (3-methyloxetan-3-yl) acetamide (92);
n-cyclopropyl-2- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -N-methylacetamide (93);
6- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) -8- (trideuteromethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridine (117);
6- (3-ethyl-5- (piperidin-4-yl) -1H-indol-2-yl) -8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (158);
6- (3- (2, 2-difluoroethyl) -5- (piperidin-4-yl) -1H-indol-2-yl) -8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (161);
6- (5- (1-isopentylpiperidin-4-yl) -3-isopropyl-1H-indol-2-yl) -8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (165);
6- (3-isopropyl-5- (1- (2-methoxyethyl) piperidin-4-yl) -1H-indol-2-yl) -8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (166);
4- ((2- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) ethyl) sulfonyl) morpholine (167);
2- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) ethane-1-sulfonamide (168);
2-cyano-2- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -N, N-dimethylacetamide (169);
2- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) propionitrile (170);
1- ((4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) methyl) cyclopropane-1-carbonitrile (171-;
6- (3-isopropyl-5- (1- (2- (phenylsulfonyl) ethyl) piperidin-4-yl) -1H-indol-2-yl) -8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (173);
2- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -N-methylethane-1-sulfonamide (174);
2- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -N, N-dimethylethane-1-sulfonamide (175);
n- (2- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) ethyl) methanesulfonamide (176);
6- (3-isopropyl-5- (1- (2- (methylsulfonyl) ethyl) piperidin-4-yl) -1H-indol-2-yl) -8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (177);
6- (3-isopropyl-5- (1- (3- (methylsulfonyl) propyl) piperidin-4-yl) -1H-indol-2-yl) -8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (178);
1- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) - [1, 4 '-bipiperidin ] -1' -yl) ethan-1-one (179);
4- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidine-1-carbonyl) -1-methylpyrrolidin-2-one (243);
2- (4- (3-ethyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -N, N-dimethylacetamide (337);
2- (4- (3-ethyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -N-methylacetamide (338);
6- (3-ethyl-5- (1- (2- (methylsulfonyl) ethyl) piperidin-4-yl) -1H-indol-2-yl) -8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (339);
2- (4- (3-ethyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) acetamide (340);
6- (3-ethyl-5- (1- (2-methoxyethyl) piperidin-4-yl) -1H-indol-2-yl) -8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (341);
1- (4- (3-ethyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -2-methylpropan-2-ol (342);
2- (4- (3- (2, 2-difluoroethyl) -2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -N, N-dimethylacetamide (343);
2- (4- (3- (2, 2-difluoroethyl) -2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -N-methylacetamide (344);
6- (3-isopropyl-5- (1- (oxetan-3-yl) piperidin-4-yl) -1H-indol-2-yl) -8- (trideuteromethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridine (357);
6- (5- (1- (2, 2-difluoroethyl) piperidin-4-yl) -3-isopropyl-1H-indol-2-yl) -8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (385);
6- (3-isopropyl-5- (1- ((1-methyl-1H-1, 2, 4-triazol-3-yl) methyl) piperidin-4-yl) -1H-indol-2-yl) -8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (386);
6- (3-isopropyl-5- (1- ((2-methoxypyrimidin-5-yl) methyl) piperidin-4-yl) -1H-indol-2-yl) -8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (387);
2- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) ethan-1-ol (388);
6- (3-isopropyl-5- (1- ((1-methyl-1H-pyrazol-5-yl) methyl) piperidin-4-yl) -1H-indol-2-yl) -8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (389);
3- ((4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) methyl) -1, 2, 4-oxadiazole (390);
3- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) propan-1-ol (391);
6- (3-isopropyl-5- (1- ((4-methyl-4H-1, 2, 4-triazol-3-yl) methyl) piperidin-4-yl) -1H-indol-2-yl) -8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (392);
6- (3-isopropyl-5- (1- (tetrahydrofuran-3-yl) piperidin-4-yl) -1H-indol-2-yl) -8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (393);
6- (3-isopropyl-5- (1- (tetrahydro-2H-pyran-3-yl) piperidin-4-yl) -1H-indol-2-yl) -8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (394);
3- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) tetrahydrothiophene 1, 1-dioxide (395);
6- (3-isopropyl-5- (1- (pyrimidin-2-ylmethyl) piperidin-4-yl) -1H-indol-2-yl) -8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (396);
4- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) butan-1-ol (397);
6- (5- (1- (2, 6-difluorobenzyl) piperidin-4-yl) -3-isopropyl-1H-indol-2-yl) -8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (398);
6- (5- (1- ((3, 5-dimethyl-1H-pyrazol-4-yl) methyl) piperidin-4-yl) -3-isopropyl-1H-indol-2-yl) -8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (399);
(3, 5-difluoro-4- ((4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) methyl) phenyl) methanol (400);
3, 5-difluoro-4- ((4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) methyl) benzonitrile (401);
6- (3-isopropyl-5- (1- (pyrimidin-5-ylmethyl) piperidin-4-yl) -1H-indol-2-yl) -8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (402);
4- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) cyclohex-1-ol (403);
6- (3-isopropyl-5- (1- ((1-methyl-1H-1, 2, 4-triazol-5-yl) methyl) piperidin-4-yl) -1H-indol-2-yl) -8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (404);
6- (5- (1- ((1, 3-dimethyl-1H-pyrazol-5-yl) methyl) piperidin-4-yl) -3-isopropyl-1H-indol-2-yl) -8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (405);
4- ((4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) methyl) thiazole (406);
4- ((4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) methyl) -5-methylthiazole (407);
2- ((4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) methyl) thiazole (408);
6- (3-isopropyl-5- (1- ((3-methyl-1H-pyrazol-5-yl) methyl) piperidin-4-yl) -1H-indol-2-yl) -8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (409);
6- (5- (1- ((1, 5-dimethyl-1H-pyrazol-3-yl) methyl) piperidin-4-yl) -3-isopropyl-1H-indol-2-yl) -8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (410);
4- ((4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) methyl) -1, 2, 3-thiadiazole (411);
6- (3-isopropyl-5- (1- (pyridazin-3-ylmethyl) piperidin-4-yl) -1H-indol-2-yl) -8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (412);
(2- ((4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) methyl) pyrimidin-5-yl) methanol (413);
6- (3-isopropyl-5- (1- ((2-methylpyrimidin-5-yl) methyl) piperidin-4-yl) -1H-indol-2-yl) -8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (414);
6- (3-isopropyl-5- (1- ((2-methylpyrimidin-4-yl) methyl) piperidin-4-yl) -1H-indol-2-yl) -8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (415);
2- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -1-methylcyclopentane-1-carbonitrile (416-);
6- (3-isopropyl-5- (1- (1- (6-methylpyridazin-3-yl) ethyl) piperidin-4-yl) -1H-indol-2-yl) -8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (418);
6- (3-isopropyl-5- (1- (1- (1-methyl-1H-pyrazol-4-yl) ethyl) piperidin-4-yl) -1H-indol-2-yl) -8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (419);
6- (5- (1- (1- (1H-pyrazol-5-yl) ethyl) piperidin-4-yl) -3-isopropyl-1H-indol-2-yl) -8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (420);
6- (3-isopropyl-5- (1- (1- (pyrimidin-2-yl) ethyl) piperidin-4-yl) -1H-indol-2-yl) -8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (421);
6- (3-isopropyl-5- (1- (1- (methylsulfonyl) propan-2-yl) piperidin-4-yl) -1H-indol-2-yl) -8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (422);
3- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) butyronitrile (423);
6- (3-isopropyl-5- (1- ((5-methylpyrazin-2-yl) methyl) piperidin-4-yl) -1H-indol-2-yl) -8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (424);
6- (3-isopropyl-5- (1- (tetrahydro-2H-thiopyran-4-yl) piperidin-4-yl) -1H-indol-2-yl) -8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (425);
1- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -2- (1H-tetrazol-5-yl) ethan-1-one (426);
n, N-diethyl-2- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) propane-1-sulfonamide (427);
6- (5- (1- (1- (butylsulfonyl) propan-2-yl) piperidin-4-yl) -3-isopropyl-1H-indol-2-yl) -8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (428);
6- (3-isopropyl-5- (1- (pyrazin-2-ylmethyl) piperidin-4-yl) -1H-indol-2-yl) -8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (429);
4- ((2- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) propyl) sulfonyl) morpholine (430);
6- (3-isopropyl-5- (1- (1- (piperidin-1-ylsulfonyl) propan-2-yl) piperidin-4-yl) -1H-indol-2-yl) -8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (431);
3- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) pentane-1, 5-diol (432);
6- (3-isopropyl-5- (1- ((2-methyl-2H-tetrazol-5-yl) methyl) piperidin-4-yl) -1H-indol-2-yl) -8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (433);
6- (3-isopropyl-5- (1- ((1-methyl-1H-1, 2, 3-triazol-4-yl) methyl) piperidin-4-yl) -1H-indol-2-yl) -8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (434);
3- ((4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) methyl) -5-methylisoxazole (435);
5- ((4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) methyl) thiazole (436);
6- (3-isopropyl-5- (1- ((1-methyl-1H-pyrazol-3-yl) methyl) piperidin-4-yl) -1H-indol-2-yl) -8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (437);
6- (5- (1- ((4, 6-dimethoxypyrimidin-2-yl) methyl) piperidin-4-yl) -3-isopropyl-1H-indol-2-yl) -8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (438);
5-cyclopropyl-2- ((4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) methyl) oxazole (439);
2- ((4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) methyl) oxazole (440);
6- (3-isopropyl-5- (1- (3, 3, 3-trifluoropropyl) piperidin-4-yl) -1H-indol-2-yl) -8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (537);
(3- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) cyclobutyl) carbamic acid tert-butyl ester (538);
ethyl 3- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) cyclobutane-1-carboxylate (539);
6- (3-isopropyl-5- (1- (tetrahydrofuran-3-yl) piperidin-4-yl) -1H-indol-2-yl) -8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (540-;
6- (3-ethyl-5- (1- (oxetan-3-yl) piperidin-4-yl) -1H-indol-2-yl) -8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (596);
6- (3- (2, 2-difluoroethyl) -5- (1- (oxetan-3-yl) piperidin-4-yl) -1H-indol-2-yl) -8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (597);
2- (4, 4-difluoropiperidin-1-yl) -1- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) ethan-1-one (602);
1- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -2- (pyrazin-2-yl) ethan-1-one (603);
(4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) (1- (pyrazin-2-yl) cyclopropyl) methanone (604);
1- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -2- (2-methyl-2H-tetrazol-5-yl) ethan-1-one (605);
1- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -2- (methylsulfonyl) ethan-1-one (606);
n- (2- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -2-oxoethyl) methanesulfonamide (607);
1- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -3- (methylsulfonyl) propan-1-one (608);
6- (3-isopropyl-5- (1- ((2-methyl-1H-imidazol-4-yl) methyl) piperidin-4-yl) -1H-indol-2-yl) -8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (620);
(4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) (2, 2, 3, 3-tetramethylcyclopropyl) methanone (621);
((2S, 4R) -4-hydroxypyrrolidin-2-yl) (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) methanone (622);
((2S, 3R) -3-hydroxypyrrolidin-2-yl) (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) methanone (623);
((2S, 4S) -4-hydroxypyrrolidin-2-yl) (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) methanone (624);
((2R, 4R) -4-hydroxypyrrolidin-2-yl) (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) methanone (625);
(4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) ((2S, 4R) -4-methoxypyrrolidin-2-yl) methanone (626);
((2S, 4R) -4-fluoropyrrolidin-2-yl) (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) methanone (627);
1- ((2S, 4R) -4-hydroxy-2- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidine-1-carbonyl) pyrrolidin-1-yl) ethan-1-one (628);
2- (dimethylamino) -1- (4- (3-ethyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) ethan-1-one (703);
1- (4- (3-ethyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -2- (methylamino) ethan-1-one (704);
(R) -1- (4- (3- (2, 2-difluoroethyl) -2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -3-hydroxybutan-1-one (705);
1- (4- (3- (2, 2-difluoroethyl) -2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -2- (methylamino) ethan-1-one (706);
(S) -1- (4- (3- (2, 2-difluoroethyl) -2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -3-hydroxybutan-1-one (707);
1- (4- (3- (2, 2-difluoroethyl) -2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -2- (dimethylamino) ethan-1-one (712);
2- ((2-hydroxyethyl) (methyl) amino) -1- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) ethan-1-one (714);
2- (cyclopropyl (2-hydroxyethyl) amino) -1- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) ethan-1-one (715);
2- (3, 3-difluoropyrrolidin-1-yl) -1- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) ethan-1-one (716);
2- (1, 1-thiomorpholino) -1- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) ethan-1-one (717);
1- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -2- ((1-methylcyclopropyl) amino) ethan-1-one (768);
1- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -2- (piperidin-1-yl) ethan-1-one (769);
1- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -2- (pyrrolidin-1-yl) ethan-1-one (770);
1- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -2- (2-oxa-6-azaspiro [3.3] hept-6-yl) ethan-1-one (771);
1- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -2- (4- (2-methoxyethyl) piperazin-1-yl) ethan-1-one (772);
1- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -2- (4-methoxypiperidin-1-yl) ethan-1-one (773);
(S) -2- (3-hydroxypyrrolidin-1-yl) -1- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) ethan-1-one (774);
(S) -2- (3-hydroxypiperidin-1-yl) -1- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) ethan-1-one (775);
(R) -2- (3-hydroxypyrrolidin-1-yl) -1- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) ethan-1-one (776);
2- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -1- (3- (methylsulfonyl) azetidin-1-yl) ethan-1-one (782);
1- (1, 1-dioxothiazolidin-3-yl) -2- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) ethan-1-one (783-;
2- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -N- (2- (methylthio) ethyl) acetamide (785);
1- ((2R, 4R) -2- (hydroxymethyl) -4-methoxypyrrolidin-1-yl) -2- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) ethan-1-one (786);
N- (2-hydroxyethyl) -2- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -N-methylacetamide (787);
N-ethyl-N- (2-hydroxyethyl) -2- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) acetamide (788);
n- (2-hydroxyethyl) -2- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -N-propylacetamide (789);
(R) -1- (2- (hydroxymethyl) pyrrolidin-1-yl) -2- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) ethan-1-one (790);
2- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -N-methyl-N- (tetrahydro-2H-pyran-4-yl) acetamide (791);
n- (3-hydroxypropyl) -2- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -N-methylacetamide (792);
2- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -N-methyl-N- (tetrahydrofuran-3-yl) acetamide (793);
N- (2- (1-hydroxycyclopentyl) ethyl) -2- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -N-methylacetamide (794);
(R) -1- (3- (hydroxymethyl) morpholino) -2- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) ethan-1-one (795);
n- (2-hydroxy-2-methylpropyl) -2- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -N-methylacetamide (796);
(S) -1- (3- (hydroxymethyl) morpholino) -2- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) ethan-1-one (797);
(S) -2- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -N-methyl-N- (tetrahydrofuran-3-yl) acetamide (798);
1- ((2R, 4R) -2- (hydroxymethyl) -4-methylpyrrolidin-1-yl) -2- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) ethan-1-one (799);
n- (2-hydroxyethyl) -2- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -N- (2-methylbutyl) acetamide (800);
N-cyclopropyl-N- (2-hydroxyethyl) -2- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) acetamide (801);
1- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -3-morpholinopropan-1-one (882);
3- (cyclopropyl (2-hydroxyethyl) amino) -1- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-one (883);
3- (1, 1-thiomorpholino) -1- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) propan-1-one (884); or
4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidine-1-carboxamidine (994).
One embodiment provides a compound of formula (I) or a salt thereof, wherein the compound has the structure of formula (I-4):
Figure BDA0001979596660000461
and R is1、R3、R4、R5M and n are defined in the first or second aspect. In this embodiment include those wherein R1is-CH2CH3、-CH(CH3)2or-CH2CHF2The compound of (1). Included in this embodiment are compounds wherein R is3Is H, -CH2CH(CH3)2、-CH2CN、-CH2C(CH3)2OH、-CH2CH2OCH3、-CH2CH2NH(CH3)、-CH2CH2S(O)2CH3、-CH(CH3)CH2S(O)2CH3、-CH2C(O)NH2、-CH2C(O)NH(CH3)、-CH2C(O)N(CH3)2、-CH2C(O)NH(CH2C(CH3)2OH)、-CH2C(O)N(CH3)(CH2CH3)、-C(O)CH2S(O)2CH3、-C(O)CH2OCH3、-C(O)CH2NH(CH3)、-C(O)CH2NH(CH2CH2OCH3)、-C(O)CH2N(CH3)2、-C(O)CH2CH2OCH3、-C(O)CH2CH2N(CH3)2、-C(O)CH2CH2CH2S(O)2NH2、-C(O)CH2C(CH3)2OH or-L1-A；L1is-CH2-、-C(O)-、-C(O)CH2-、-C(O)CH2CH2-、-C(O)CH2NH-、-CH2C (O) -or-CH2C (O) NH-; and A is azetidinyl, cyclobutyl, dioxanyl, dioxotetrahydrothiopyranyl, dioxothiomorpholinyl, morpholinyl, oxetanyl, piperazinonyl, pyrrolidinonyl, pyrrolidinyl, tetrahydrofuranyl or tetrahydropyranyl, each of which is substituted by-L 2-RaAnd 0 to 1RbSubstitution; l is2Is a bond; raIs H, F, C1-2Alkyl, -CN, -OH, -OCH3、-C(O)CH3or-C (O) OC (CH)3)3(ii) a And R isbIs F or-CH3. Also included in this embodiment are compounds wherein R is1is-CH (CH)3)2(ii) a m is 0; and n is 0.
One embodiment provides a compound of formula (I) or a salt thereof, wherein the compound is:
6- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) -8-methoxy- [1, 2, 4] triazolo [1, 5-a ] pyridine (5);
2- (4- (3-isopropyl-2- (8-methoxy- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) acetonitrile (21);
2- (4- (3-isopropyl-2- (8-methoxy- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) acetamide (22);
2- (4- (3-isopropyl-2- (8-methoxy- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -N-methylacetamide (23);
1- (4- (3-isopropyl-2- (8-methoxy- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -2-methylpropan-2-ol (24);
2- (4- (3-isopropyl-2- (8-methoxy- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -N, N-dimethylacetamide (25);
6- (3-isopropyl-5- (1- (oxetan-3-yl) piperidin-4-yl) -1H-indol-2-yl) -8-methoxy- [1, 2, 4] triazolo [1, 5-a ] pyridine (44);
6- (3-isopropyl-5- (1- (tetrahydro-2H-pyran-4-yl) piperidin-4-yl) -1H-indol-2-yl) -8-methoxy- [1, 2, 4] triazolo [1, 5-a ] pyridine (45);
1- (4- (3-isopropyl-2- (8-methoxy- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -2- (methylamino) ethan-1-one (62);
1- (4- (3-isopropyl-2- (8-methoxy- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -2-methoxyethan-1-one (63);
2- (dimethylamino) -1- (4- (3-isopropyl-2- (8-methoxy- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) ethan-1-one (67);
6- (3- (2, 2-difluoroethyl) -5- (piperidin-4-yl) -1H-indol-2-yl) -8-methoxy- [1, 2, 4] triazolo [1, 5-a ] pyridine (156);
6- (3-ethyl-5- (piperidin-4-yl) -1H-indol-2-yl) -8-methoxy- [1, 2, 4] triazolo [1, 5-a ] pyridine (157);
6- (3-isopropyl-5- (1- (2- (methylsulfonyl) ethyl) piperidin-4-yl) -1H-indol-2-yl) -8-methoxy- [1, 2, 4] triazolo [1, 5-a ] pyridine (263);
6- (3-isopropyl-5- (1- (1- (methylsulfonyl) propan-2-yl) piperidin-4-yl) -1H-indol-2-yl) -8-methoxy- [1, 2, 4] triazolo [1, 5-a ] pyridine (264);
6- (3-isopropyl-5- (1- (1- (methylsulfonyl) propan-2-yl) piperidin-4-yl) -1H-indol-2-yl) -8-methoxy- [1, 2, 4] triazolo [1, 5-a ] pyridine (265);
6- (3-isopropyl-5- (1- (2-methoxyethyl) piperidin-4-yl) -1H-indol-2-yl) -8-methoxy- [1, 2, 4] triazolo [1, 5-a ] pyridine (266);
2- (4- (3- (2, 2-difluoroethyl) -2- (8-methoxy- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -N, N-dimethylacetamide (329);
2- (4- (3- (2, 2-difluoroethyl) -2- (8-methoxy- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -N-methylacetamide (330);
2- (4- (3-ethyl-2- (8-methoxy- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -N-methylacetamide (331);
6- (3-ethyl-5- (1- (2- (methylsulfonyl) ethyl) piperidin-4-yl) -1H-indol-2-yl) -8-methoxy- [1, 2, 4] triazolo [1, 5-a ] pyridine (332);
2- (4- (3-ethyl-2- (8-methoxy- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) acetamide (333);
1- (4- (3-ethyl-2- (8-methoxy- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -2-methylpropan-2-ol (334);
2- (4- (3-ethyl-2- (8-methoxy- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -N, N-dimethylacetamide (335);
6- (3-ethyl-5- (1- (2-methoxyethyl) piperidin-4-yl) -1H-indol-2-yl) -8-methoxy- [1, 2, 4] triazolo [1, 5-a ] pyridine (336);
1- (4- (3- (2, 2-difluoroethyl) -2- (8-methoxy- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -2-methylpropan-2-ol (349);
4- (4- (3-isopropyl-2- (8-methoxy- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) tetrahydro-2H-thiopyran 1, 1-dioxide (561);
6- (5- (1- (2, 2-dimethyltetrahydro-2H-pyran-4-yl) piperidin-4-yl) -3-isopropyl-1H-indol-2-yl) -8-methoxy- [1, 2, 4] triazolo [1, 5-a ] pyridine (562-);
(R) -3- ((4- (3-isopropyl-2- (8-methoxy- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) methyl) morpholine (565);
6- (3-isopropyl-5- (1- ((3-methyloxetan-3-yl) methyl) piperidin-4-yl) -1H-indol-2-yl) -8-methoxy- [1, 2, 4] triazolo [1, 5-a ] pyridine (566);
3- (4- (3-isopropyl-2- (8-methoxy- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) cyclobutane-1-carbonitrile (567);
6- (3-isopropyl-5- (1- (tetrahydrofuran-3-yl) piperidin-4-yl) -1H-indol-2-yl) -8-methoxy- [1, 2, 4] triazolo [1, 5-a ] pyridine (568 569);
2- (4- (3-isopropyl-2- (8-methoxy- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -N-methylethyl-1-amine (570);
6- (3- (2, 2-difluoroethyl) -5- (1- (oxetan-3-yl) piperidin-4-yl) -1H-indol-2-yl) -8-methoxy- [1, 2, 4] triazolo [1, 5-a ] pyridine (598);
6- (3-ethyl-5- (1- (oxetan-3-yl) piperidin-4-yl) -1H-indol-2-yl) -8-methoxy- [1, 2, 4] triazolo [1, 5-a ] pyridine (600);
(4- (3-isopropyl-2- (8-methoxy- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) (tetrahydrofuran-2-yl) methanone (663);
1- (4- (3-isopropyl-2- (8-methoxy- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -3-methoxypropan-1-one (664);
4- (4- (3-isopropyl-2- (8-methoxy- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -4-oxobutane-1-sulfonamide (665);
1- (4- (3-isopropyl-2- (8-methoxy- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -2- (tetrahydro-2H-pyran-4-yl) ethan-1-one (666);
3- (dimethylamino) -1- (4- (3-isopropyl-2- (8-methoxy- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-one (667);
1- (4- (3-isopropyl-2- (8-methoxy- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -2- (methylsulfonyl) ethan-1-one (668);
3-hydroxy-1- (4- (3-isopropyl-2- (8-methoxy- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -3-methylbutan-1-one (669);
(S) -1- (2- (4- (3-isopropyl-2- (8-methoxy- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidine-1-carbonyl) pyrrolidin-1-yl) ethan-1-one (670);
1- (3- (4- (3-isopropyl-2- (8-methoxy- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -3-oxopropyl) pyrrolidin-2-one (671);
(4- (3-isopropyl-2- (8-methoxy- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) (1-methylpyrrolidin-3-yl) methanone (672);
1- (4- (3-isopropyl-2- (8-methoxy- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -2-morpholinoethan-1-one (673);
((2S, 4R) -4-hydroxypyrrolidin-2-yl) (4- (3-isopropyl-2- (8-methoxy- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) methanone (674);
(4- (3-isopropyl-2- (8-methoxy- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) ((2S, 4R) -4-methoxypyrrolidin-2-yl) methanone (675);
(4- (3-isopropyl-2- (8-methoxy- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) (1-methylpyrrolidin-3-yl) methanone (676);
4- (4- (3-isopropyl-2- (8-methoxy- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidine-1-carbonyl) -1-methylpyrrolidin-2-one (677);
4- (4- (3-isopropyl-2- (8-methoxy- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidine-1-carbonyl) -1-methylpyrrolidin-2-one (678);
(4- (3-isopropyl-2- (8-methoxy- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) (1-methylpyrrolidin-3-yl) methanone (679);
2- (dimethylamino) -1- (4- (3-ethyl-2- (8-methoxy- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) ethan-1-one (701);
1- (4- (3-ethyl-2- (8-methoxy- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -2- (methylamino) ethan-1-one (702);
1- (4- (3-isopropyl-2- (8-methoxy- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -2- ((2-methoxyethyl) amino) ethan-1-one (780);
1- (4- (3-isopropyl-2- (8-methoxy- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -2- ((3-methyloxetan-3-yl) amino) ethan-1-one (781);
2- (4- (3-isopropyl-2- (8-methoxy- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -N- (3-methyloxetan-3-yl) acetamide (854);
3- (2- (4- (3-isopropyl-2- (8-methoxy- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) acetamido) azetidine-1-carboxylic acid tert-butyl ester (855);
2- (4- (3-isopropyl-2- (8-methoxy- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -N- (4-methyltetrahydro-2H-pyran-4-yl) acetamide (856);
n- (2-hydroxy-2-methylpropyl) -2- (4- (3-isopropyl-2- (8-methoxy- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) acetamide (857);
1- (1, 1-thiomorpholino) -2- (4- (3-isopropyl-2- (8-methoxy- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) ethan-1-one (858);
n-ethyl-2- (4- (3-isopropyl-2- (8-methoxy- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -N-methylacetamide (859);
2- (4- (3-isopropyl-2- (8-methoxy- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -N- (1-methylcyclobutyl) acetamide (860);
n- ((3-ethyloxetan-3-yl) methyl) -2- (4- (3-isopropyl-2- (8-methoxy- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) acetamide (861);
2- (4- (3-isopropyl-2- (8-methoxy- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -N- ((3-methyloxetan-3-yl) methyl) acetamide (862);
(R) -1- (3-hydroxypyrrolidin-1-yl) -2- (4- (3-isopropyl-2- (8-methoxy- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) ethan-1-one (863);
1- (3-fluoroazetidin-1-yl) -2- (4- (3-isopropyl-2- (8-methoxy- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) ethan-1-one (864);
1- (3, 3-difluoroazetidin-1-yl) -2- (4- (3-isopropyl-2- (8-methoxy- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) ethan-1-one (865);
4- (2- (4- (3-isopropyl-2- (8-methoxy- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) acetyl) piperazin-2-one (866);
1- (3-hydroxyazetidin-1-yl) -2- (4- (3-isopropyl-2- (8-methoxy- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) ethan-1-one (867);
(R) -1- (3-fluoropyrrolidin-1-yl) -2- (4- (3-isopropyl-2- (8-methoxy- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) ethan-1-one (868);
1- ((2S, 6R) -2, 6-dimethylmorpholino) -2- (4- (3-isopropyl-2- (8-methoxy- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) ethan-1-one (869);
1- (azetidin-1-yl) -2- (4- (3-isopropyl-2- (8-methoxy- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) ethan-1-one (870);
(R) -2- (4- (3-isopropyl-2- (8-methoxy- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -1- (3-methylmorpholino) ethan-1-one (871);
1- (3, 3-difluoropyrrolidin-1-yl) -2- (4- (3-isopropyl-2- (8-methoxy- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) ethan-1-one (872);
1- (2, 5-dimethylpyrrolidin-1-yl) -2- (4- (3-isopropyl-2- (8-methoxy- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) ethan-1-one (873);
(S) -1- (3-hydroxypyrrolidin-1-yl) -2- (4- (3-isopropyl-2- (8-methoxy- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) ethan-1-one (874);
(S) -1- (3-fluoropyrrolidin-1-yl) -2- (4- (3-isopropyl-2- (8-methoxy- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) ethan-1-one (875);
2- (4- (4-fluoro-3-isopropyl-2- (8-methoxy- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -N, N-dimethylacetamide (991);
6- (4-fluoro-5- (1-isobutylpiperidin-4-yl) -3-isopropyl-1H-indol-2-yl) -8-methoxy- [1, 2, 4] triazolo [1, 5-a ] pyridine (992); or
6- (5- (1- (2, 2-dimethyl-1, 3-dioxan-5-yl) piperidin-4-yl) -4-fluoro-3-isopropyl-1H-indol-2-yl) -8-methoxy- [1, 2, 4] triazolo [1, 5-a ] pyridine (993).
One embodiment provides a compound of formula (I-4) or a salt thereof, wherein R1is-CH (CH)3)2(ii) a m is 0; n is 0; and R is3As defined in the first or second aspect. The compounds of this embodiment have the structure of formula (I-4 a):
Figure BDA0001979596660000521
included in this embodiment are compounds wherein R is3Is- (CR)xRx)1-2C(O)NRyRyWherein each R isxIndependently is H or-CH3(ii) a And each R yIndependently is H or-CH3. Also included in this embodiment are those in which R3is-CH2C(O)NH2、-CH2C(O)NH(CH3) or-CH2C(O)N(CH3)2The compound of (1).
One embodiment provides a compound of formula (I) or a salt thereof, wherein the compound is:
Figure BDA0001979596660000522
included in this embodiment is 2- (4- (3-isopropyl-2- (8-methoxy- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -N, N-dimethylacetamide (25). Also included in this embodiment are one or more salts of 2- (4- (3-isopropyl-2- (8-methoxy- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -N, N-dimethylacetamide.
One embodiment provides a compound of formula (I) or a salt thereof, wherein the compound has the structure of formula (I-5):
Figure BDA0001979596660000531
and R is1、R3、R4、R5M and n are defined in the first or second aspect. In this embodiment include those wherein R1is-CH (CH)3)2The compound of (1). Included in this embodiment are compounds wherein R is3Is H, -CH2CN、-CH2C(O)NH2、-CH2C(O)NH(CH3)、-CH2C(O)NH(CH2CH3)、-CH2C(O)NH(CH2CH2CN)、-CH2C(O)NH(CH2CH2CF3)、-CH2C(O)NH(CH(CH3)2)、-CH2C(O)N(CH3)CH2CH2OCH3、-CH2C(O)N(CH3)CH2CH2CN、-CH2C(O)N(CH3)CH2CH2CH2OH、-CH2CH2S(O)2NH2、-CH2CH2S(O)2CH3、-CH2C(O)NHCH(CH2CH2OH) (cyclopropyl) or-L1-A；L1is-CH2-、-CH2CH2-、-CH2C(O)-、-CH2C(O)N(CH3) -or-CH2C(O)N(CH3)CH2CH2-; a is azetidinyl, thiadiazinyl dioxide, dioxoisothiazolyl, dioxothiomorpholinyl, morpholinyl, oxetanyl, piperidinyl, pyrazolyl, pyrimidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl or triazolyl, each of which is substituted by-L 2-RaAnd 0 to 1RbSubstitution; l is2Is a bond; raIs H, F, -CH3、-CN、-CH2OH or-S (O)2CH3(ii) a And R isbIs F, -CH3、-CF3or-OCH3. Also included in this embodiment are compounds wherein R is1is-CH (CH)3)2(ii) a m is 0; and n is 0.
One embodiment provides a compound of formula (I) or a salt thereof, wherein the compound is:
6- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) -8- (methoxymethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridine (6);
2- (4- (3-isopropyl-2- (8- (methoxymethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -N, N-dimethylacetamide (198);
2- (4- (3-isopropyl-2- (8- (methoxymethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) acetamide (199);
6- (3-isopropyl-5- (1- (2- (methylsulfonyl) ethyl) piperidin-4-yl) -1H-indol-2-yl) -8- (methoxymethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridine (200);
2- (4- (3-isopropyl-2- (8- (methoxymethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) acetonitrile (201);
2- (4- (3-isopropyl-2- (8- (methoxymethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -N-methylacetamide (202);
2- (4- (3-isopropyl-2- (8- (methoxymethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) ethane-1-sulfonamide (203);
6- (3-isopropyl-5- (1- ((1-methyl-1H-1, 2, 3-triazol-4-yl) methyl) piperidin-4-yl) -1H-indol-2-yl) -8- (methoxymethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridine (470);
6- (3-isopropyl-5- (1- ((2-methylpyrimidin-5-yl) methyl) piperidin-4-yl) -1H-indol-2-yl) -8- (methoxymethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridine (471);
6- (3-isopropyl-5- (1- ((3-methyloxetan-3-yl) methyl) piperidin-4-yl) -1H-indol-2-yl) -8- (methoxymethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridine (472);
6- (3-isopropyl-5- (1- (oxetan-3-yl) piperidin-4-yl) -1H-indol-2-yl) -8- (methoxymethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridine (473);
2- (2- (4- (3-isopropyl-2- (8- (methoxymethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) ethyl) isothiazolidine 1, 1-dioxide (474);
n- (2-cyanoethyl) -2- (4- (3-isopropyl-2- (8- (methoxymethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -N-methylacetamide (811);
(S) -1- (2- (hydroxymethyl) pyrrolidin-1-yl) -2- (4- (3-isopropyl-2- (8- (methoxymethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) ethan-1-one (812);
1- (1, 1-dioxo-1, 2, 4-thiadiazinan-4-yl) -2- (4- (3-isopropyl-2- (8- (methoxymethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) ethan-1-one (813);
n- (3-hydroxypropyl) -2- (4- (3-isopropyl-2- (8- (methoxymethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -N-methylacetamide (814);
2- (4- (3-isopropyl-2- (8- (methoxymethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -N-methyl-N- (tetrahydro-2H-pyran-4-yl) acetamide (815);
n-ethyl-2- (4- (3-isopropyl-2- (8- (methoxymethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) acetamide (816);
n, N-diethyl-2- (4- (3-isopropyl-2- (8- (methoxymethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) acetamide (817);
n- (2-hydroxyethyl) -2- (4- (3-isopropyl-2- (8- (methoxymethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -N-methylacetamide (818);
N-ethyl-2- (4- (3-isopropyl-2- (8- (methoxymethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -N-methylacetamide (819);
2- (4- (3-isopropyl-2- (8- (methoxymethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -N- (2-methoxyethyl) -N-methylacetamide (820);
n-isopropyl-2- (4- (3-isopropyl-2- (8- (methoxymethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) acetamide (821);
1- ((2R, 4R) -2- (hydroxymethyl) -4-methoxypyrrolidin-1-yl) -2- (4- (3-isopropyl-2- (8- (methoxymethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) ethan-1-one (822);
(S) -2- (4- (3-isopropyl-2- (8- (methoxymethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -N-methyl-N- (tetrahydrofuran-3-yl) acetamide (823);
1- ((2R, 4R) -2- (hydroxymethyl) -4- (trifluoromethyl) pyrrolidin-1-yl) -2- (4- (3-isopropyl-2- (8- (methoxymethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) ethan-1-one (824);
N-ethyl-N- (2-hydroxyethyl) -2- (4- (3-isopropyl-2- (8- (methoxymethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) acetamide (825);
2- (4- (3-isopropyl-2- (8- (methoxymethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -1- (3- (methylsulfonyl) azetidin-1-yl) ethan-1-one (826);
1- (1, 1-thiomorpholino) -2- (4- (3-isopropyl-2- (8- (methoxymethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) ethan-1-one (827);
n- (2-hydroxy-2-methylpropyl) -2- (4- (3-isopropyl-2- (8- (methoxymethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -N-methylacetamide (828);
(R) -1- (3- (hydroxymethyl) morpholino) -2- (4- (3-isopropyl-2- (8- (methoxymethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) ethan-1-one (829);
1- (4, 4-difluoropiperidin-1-yl) -2- (4- (3-isopropyl-2- (8- (methoxymethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) ethan-1-one (830);
1- (3, 3-dimethylazetidin-1-yl) -2- (4- (3-isopropyl-2- (8- (methoxymethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) ethan-1-one (831);
2- (4- (3-isopropyl-2- (8- (methoxymethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -N- (3, 3, 3-trifluoropropyl) acetamide (832);
1- (3, 3-difluoropyrrolidin-1-yl) -2- (4- (3-isopropyl-2- (8- (methoxymethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) ethan-1-one (833);
n- (1-cyclopropyl-3-hydroxypropyl) -2- (4- (3-isopropyl-2- (8- (methoxymethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) acetamide (834);
(R) -1- (2- (hydroxymethyl) pyrrolidin-1-yl) -2- (4- (3-isopropyl-2- (8- (methoxymethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) ethan-1-one (835);
n- (2- (1H-pyrazol-4-yl) ethyl) -2- (4- (3-isopropyl-2- (8- (methoxymethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -N-methylacetamide (836);
1- ((2R, 4R) -2- (hydroxymethyl) -4-methylpyrrolidin-1-yl) -2- (4- (3-isopropyl-2- (8- (methoxymethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) ethan-1-one (837);
1- (2- (4- (3-isopropyl-2- (8- (methoxymethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) acetyl) azetidine-3-carbonitrile (838);
2- (4- (3-isopropyl-2- (8- (methoxymethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -N-methyl-N- (tetrahydrofuran-3-yl) acetamide (839);
1- (3, 3-difluoroazetidin-1-yl) -2- (4- (3-isopropyl-2- (8- (methoxymethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) ethan-1-one (840);
1- ((2S, 4S) -2- (hydroxymethyl) -4- (trifluoromethyl) pyrrolidin-1-yl) -2- (4- (3-isopropyl-2- (8- (methoxymethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) ethan-1-one (841); or
N- (2-cyanoethyl) -2- (4- (3-isopropyl-2- (8- (methoxymethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) acetamide (842).
One embodiment provides a compound of formula (I) or a salt thereof, wherein the compound has the structure of formula (I-6):
Figure BDA0001979596660000561
and R is1、R3、R4、R5M and n are defined in the first or second aspect. In this embodiment include those wherein R1is-CH (CH)3)2or-CH2CHF2The compound of (1). In this embodiment is described inComprises the following compounds, wherein R3Is H, C1-5Alkyl radical, C1-2Cyanoalkyl, -CH2CH2CF3、-CH2C(CH3)2OH、-CH2CH3、-CH2CH2OCH3、-CH2N(CH3)2、-CH2C(O)NH2、-CH2C(O)NH(CH3)、-CH2C(O)N(CH3)2、-CH2C(O)N(CH3)(CH2CH2OH)、-CH2CH2S(O)2CH3、-CH2CH2S(O)2NH2、-CH2CH2S(O)2N(CH3)2、-CH2CH2NHS(O)2CH3、-CH2CH2N(CH3)S(O)2CH3、-C(O)OCH2CH2NH2、-C(O)OCH2CH2N(CH3)2、-C(O)OCH2CH2N(CH2CH3)2、-C(O)OC(CH3)3、-C(O)NHCH2C(CH3)3、-C(O)NH(CH2CH2NH2)、-C(O)NH(CH2CH2N(CH3)2)、-C(O)NH(CH2CH2CH2NH2)、-C(O)N(CH3)CH2CH2NH2、-C(O)CH2NHCH(CH3)2、-C(O)CH2NHC(CH3)3、-C(O)CH2NH(CH3)、-C(O)CH2NH(CH2CN)、-C(O)CH2NH(CH2CH3)、-C(O)CH2NH(CH2CH2OH)、-C(O)CH2NH(CH2CH2OCH3)、-C(O)CH2NH(CH2CH2F)、-C(O)CH2NH(CH2CH2CH3)、-C(O)CH2NH(CH2CH(CH3)2)、-C(O)CH2NH(CH2CF3)、-C(O)CH2NH(CH2C(O)NH2)、-C(O)CH2N(CH3)CH2CH3、-C(O)CH2N(CH3)CH2CH2CN、-C(O)CH2N(CH3)CH2CH2CH3、-C(O)CH2N(CH3)CH2CH(CH3)2、-C(O)CH2N(CH3)CH2C(O)N(CH3)2、-C(O)CH2N(CH3)CH(CH3)2、-C(O)CH2N(CH3)2、-C(O)CH2N(CH3)(CH2CH2OH)、-C(O)CH2N(CH3)(CH2CH2OCH3)、-C(O)CH2N(CH2CH3)2、-C(O)CH2N(CH2CH2OCH3)2、-C(O)CH2CH2NH(CH3)、-C(O)CH2CH2NH(CH2CH3)、-C(O)CH2CH2NH(CH2CH2OH)、-C(O)CH2CH2NH(CH2CH2OCH3)、-C(O)CH2CH2NH(CH2CH2F)、-C(O)CH2CH2NH(CH2CH2CH3)、-C(O)CH2CH2NH(CH2C(O)NH2)、-C(O)CH2CH2NH(CH2C(CH3)3)、-C(O)CH2CH2NH(CH(CH3)2)、-C(O)CH2CH2N(CH3)CH2CH2OH、-C(O)CH2CH2N(CH3)CH2CH2OCH3、-C(O)CH2CH2N(CH3)CH2C(O)N(CH3)2、-C(O)CH2CH2N(CH3)(CH2CH3)、-C(O)CH2CH2N(CH3)(CH2CH2CH3)、-C(O)CH2CH2N(CH3)(CH(CH3)2) or-L1-A；L1is-CH2-、-CH2CH2-、-CH(CN)-、-C(O)-、-C(O)CH2-、-C(O)CH2CH2-、-C(O)CH2NH-、-C(O)CH2N(CH3)-、-C(O)CH2CH2NH-、-C(O)CH2CH2N(CH3)-、-C(O)CH2NHCH2-、-C(O)CH2CH2NHCH2-，-CH2C(O)-、-CH2C(O)NH-、-C(O)NH-、-C(O)NHCH2-、-C(O)NHCH2CH2-、-C(O)O-、-C(O)OCH2-or-C (O) OCH2CH2-; and A is azepinyl, azetidinyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclopropyl, dioxoisothiazolidinyl, dioxotetrahydrothiopyranyl, dioxothiomorpholinyl, imidazolyl, morpholinyl, octahydropyrrolo [3, 4-b ] or ]Pyridyl, oxa-azaspiro [3.3]Hept-6-yl, oxetanyl, piperazinonyl, piperazinyl, piperidinonyl, piperidinyl, pyridinyl, pyrimidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, triazolonyl or triazolyl; azetidinyl, cyclobutyl, dioxanyl, dioxotetrahydrothiopyranyl, dioxothiomorpholinyl, morpholinyl, oxetanyl, piperazinonyl, pyrrolidinonyl, pyrrolidinyl, tetrahydrofuranyl or tetrahydropyranyl, each of which is substituted by-L2-RaAnd 0 to 1RbSubstitution; l is2Is a bond; raIs H, F, C1-3Alkyl radical, C1-2Hydroxyalkyl, -CH2OCH3、-CH2CH2OCH3、-OH、-OCH3、-NH2、-C(O)CH3、-C(O)CH(CH2CH3)2、-C(O)NH2、-C(O)N(CH2CH3)2、-C(O)OC(CH3)3、-S(O)2CH3Or a pyridyl group; and R isbIs F or-CH3. Also included in this embodiment are compounds wherein R is1is-CH (CH)3)2(ii) a m is 0; and n is 0.
One embodiment provides a compound of formula (I) or a salt thereof, wherein the compound is:
6- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) -7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (4);
2- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) acetonitrile (13);
3- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) propionitrile (14);
2- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) acetamide (15);
2- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -N-methylacetamide (16);
1- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -2-methylpropan-2-ol (17);
6- (3-isopropyl-5- (1- (2- (methylsulfonyl) ethyl) piperidin-4-yl) -1H-indol-2-yl) -7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (18);
2- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) ethane-1-sulfonamide (19);
4- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) tetrahydro-2H-thiopyran 1, 1-dioxide (20);
6- (3-isopropyl-5- (1- (oxetan-3-yl) piperidin-4-yl) -1H-indol-2-yl) -7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (38);
6- (5- (1- ((1H-1, 2, 3-triazol-5-yl) methyl) piperidin-4-yl) -3-isopropyl-1H-indol-2-yl) -7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (39);
6- (3-isopropyl-5- (1- (tetrahydro-2H-pyran-4-yl) piperidin-4-yl) -1H-indol-2-yl) -7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (40);
2- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -N, N-dimethylacetamide (41);
6- (3-isopropyl-5- (1- ((1-methyl-1H-1, 2, 3-triazol-4-yl) methyl) piperidin-4-yl) -1H-indol-2-yl) -7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (42);
6- (3-isopropyl-5- (1- ((1-methyl-1H-1, 2, 4-triazol-3-yl) methyl) piperidin-4-yl) -1H-indol-2-yl) -7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (43);
1- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -2- (dimethylamino) ethan-1-one (66);
6- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) -5, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (110);
6- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) -2, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (124);
6- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) -2, 7-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (125);
N- (2- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) ethyl) methanesulfonamide (204);
n- (2- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) ethyl) -N-methyl methanesulfonamide (205);
2- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -N, N-dimethylethane-1-sulfonamide (206);
2- (2- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) ethyl) isothiazolidine 1, 1-dioxide (475);
2- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -2- (3-methyloxetan-3-yl) acetonitrile (476);
1- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -2-morpholinoethan-1-one (477);
6- (5- (1-isobutylpiperidin-4-yl) -3-isopropyl-1H-indol-2-yl) -7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (478);
6- (5- (1-isopentylpiperidin-4-yl) -3-isopropyl-1H-indol-2-yl) -7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (479);
6- (5- (1-ethylpiperidin-4-yl) -3-isopropyl-1H-indol-2-yl) -7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (480);
6- (3-isopropyl-5- (1-propylpiperidin-4-yl) -1H-indol-2-yl) -7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (481);
6- (5- (1-ethylpiperidin-4-yl) -3-isopropyl-1H-indol-2-yl) -7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (482);
5- ((4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) methyl) -2, 4-dihydro-3H-1, 2, 4-triazol-3-one (483);
6- (3-isopropyl-5- (1- (3, 3, 3-trifluoropropyl) piperidin-4-yl) -1H-indol-2-yl) -7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (484);
6- (3-isopropyl-5- (1-methylpiperidin-4-yl) -1H-indol-2-yl) -7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (485);
6- (3-isopropyl-5- (1- (2-methoxyethyl) piperidin-4-yl) -1H-indol-2-yl) -7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (486);
4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidine-1-carboxylic acid tert-butyl ester (609);
1- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -3-morpholinopropan-1-one (610);
2- (bis (2-methoxyethyl) amino) -1- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) ethan-1-one (718);
1- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -2- (3-hydroxypyrrolidin-1-yl) ethan-1-one (719);
1- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -2- (2, 6-dimethylmorpholino) ethan-1-one (720);
1- (1- (2- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -2-oxoethyl) piperidin-3-yl) -2-ethylbutan-1-one (721);
(S) -1- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -2- (2- (methoxymethyl) pyrrolidin-1-yl) ethan-1-one (722);
1- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -2- (isobutyl (methyl) amino) ethan-1-one (723);
1- (2- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -2-oxoethyl) piperidine-4-carboxamide (724);
4- (2- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -2-oxoethyl) piperazin-2-one (725);
3- ((2- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -2-oxoethyl) (methyl) amino) propionitrile (726);
2- (cyclopentylamino) -1- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) ethan-1-one (727);
2- (cyclohexylamino) -1- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) ethan-1-one (728);
1- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -2- ((4-hydroxycyclohexyl) amino) ethan-1-one (729);
2- ((cyclohexylmethyl) amino) -1- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) ethan-1-one (730);
1- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -2- (((tetrahydrofuran-2-yl) methyl) amino) ethan-1-one (731);
2- (tert-butylamino) -1- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) ethan-1-one (732);
1- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -2- (neopentylamino) ethan-1-one (733);
1- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -2- (propylamino) ethan-1-one (734);
(R) -1- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -2- (3-hydroxypyrrolidin-1-yl) ethan-1-one (735);
(S) -1- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -2- (3-hydroxypyrrolidin-1-yl) ethan-1-one (736);
1- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -2- (isopropylamino) ethan-1-one (737);
(S) -1- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -2- (3-fluoropyrrolidin-1-yl) ethan-1-one (738);
1- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -2- ((2-fluoroethyl) amino) ethan-1-one (739);
1- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -2- (ethylamino) ethan-1-one (740);
2- (4, 4-difluoropiperidin-1-yl) -1- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) ethan-1-one (741);
2- (cyclopropylamino) -1- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) ethan-1-one (742);
1- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -2- ((2-methoxyethyl) amino) ethan-1-one (743);
1- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -2- (piperidin-1-yl) ethan-1-one (744);
1- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -2- (pyrrolidin-1-yl) ethan-1-one (745);
1- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -2- (isobutylamino) ethan-1-one (746);
1- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -2- (3, 3-dimethylpiperidin-1-yl) ethan-1-one (747);
2- ((2- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -2-oxoethyl) amino) acetamide (748);
(S) -1- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -2- (2- (hydroxymethyl) pyrrolidin-1-yl) ethan-1-one (749);
1- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -2- (4-methoxypiperidin-1-yl) ethan-1-one (750);
2- (cyclohexyl (methyl) amino) -1- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) ethan-1-one (751);
2- ((2- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -2-oxoethyl) amino) acetonitrile (752);
1- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -2- (methylamino) ethan-1-one (753);
2- (azepan-1-yl) -1- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) ethan-1-one (754);
1- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -2- (4-hydroxypiperidin-1-yl) ethan-1-one (755);
1- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -2- ((2-hydroxyethyl) (methyl) amino) ethan-1-one (756);
1- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -2- ((2-hydroxyethyl) amino) ethan-1-one (757);
2- ((cyclopropylmethyl) amino) -1- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) ethan-1-one (758);
2- ((2- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -2-oxoethyl) (methyl) amino) -N, N-dimethylacetamide (759);
1- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -2- ((2-methoxyethyl) (methyl) amino) ethan-1-one (760);
1- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -2- ((2, 2, 2-trifluoroethyl) amino) ethan-1-one (761);
1- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -2- (methyl (propyl) amino) ethan-1-one (762);
2- (diethylamino) -1- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) ethan-1-one (763);
2- (cyclobutylamino) -1- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) ethan-1-one (764);
2- (azetidin-1-yl) -1- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) ethan-1-one (765);
1- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -2- (ethyl (methyl) amino) ethan-1-one (766);
1- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -2- (isopropyl (methyl) amino) ethan-1-one (767);
2- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -1-morpholinoethan-1-one (843);
1- (azetidin-1-yl) -2- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) ethan-1-one (844);
2- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -1- (3- (methylsulfonyl) azetidin-1-yl) ethan-1-one (845);
2- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -N- (3-methyloxetan-3-yl) acetamide (846);
2- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -1- (1, 1-sulfur dioxide morpholino) ethan-1-one (847);
2- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -N- (2-hydroxyethyl) -N-methylacetamide (848);
2- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -1- (2-oxa-6-azaspiro [3.3] hept-6-yl) ethan-1-one (849);
1- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -3- ((4-hydroxycyclohexyl) amino) propan-1-one (886);
1- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -3- (((tetrahydrofuran-2-yl) methyl) amino) propan-1-one (887);
(R) -1- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -3- (3-fluoropyrrolidin-1-yl) propan-1-one (888);
1- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -3- ((2-hydroxyethyl) amino) propan-1-one (889);
1- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -3- (propylamino) propan-1-one (890);
2- ((3- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -3-oxopropyl) amino) acetamide (891);
3- ((cyclopropylmethyl) amino) -1- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) propan-1-one (892);
3- (azetidin-1-yl) -1- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-one (893);
1- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -3- (ethyl (methyl) amino) propan-1-one (894);
1- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -3- (methyl (propyl) amino) propan-1-one (895);
1- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -3- (isopropyl (methyl) amino) propan-1-one (896);
2- ((3- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -3-oxopropyl) (methyl) amino) -N, N-dimethylacetamide (897);
1- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -3- ((2-methoxyethyl) (methyl) amino) propan-1-one (898);
(R) -1- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -3- (3-hydroxypyrrolidin-1-yl) propan-1-one (899);
3- (4, 4-difluoropiperidin-1-yl) -1- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) propan-1-one (900);
1- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -3- ((2-methoxyethyl) amino) propan-1-one (901);
1- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -3- (isopropylamino) propan-1-one (902);
1- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -3- (ethylamino) propan-1-one (903);
1- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -3- (piperidin-1-yl) propan-1-one (904);
1- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -3- (methylamino) propan-1-one (905);
1- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -3- (2, 6-dimethylmorpholino) propan-1-one (906);
1- (3- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -3-oxopropyl) -N, N-diethylpiperidine-3-carboxamide (907);
1- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -3- (3, 3-dimethylpiperidin-1-yl) propan-1-one (908);
1- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -3- (4-hydroxypiperidin-1-yl) propan-1-one (909);
3- (azepan-1-yl) -1- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) propan-1-one (910);
(S) -1- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -3- (2- (methoxymethyl) pyrrolidin-1-yl) propan-1-one (911);
1- (3- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -3-oxopropyl) piperidine-4-carboxamide (912);
4- (3- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -3-oxopropyl) piperazin-2-one (913);
1- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -3- ((2-hydroxyethyl) (methyl) amino) propan-1-one (914);
1- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -3- (4-methoxypiperidin-1-yl) propan-1-one (915);
1- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -3- (pyrrolidin-1-yl) propan-1-one (916);
(S) -1- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -3- (2- (hydroxymethyl) pyrrolidin-1-yl) propan-1-one (917);
3- (cyclobutylamino) -1- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) propan-1-one (918);
3- (cyclopentylamino) -1- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) propan-1-one (919);
3- (cyclohexylamino) -1- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) propan-1-one (920);
(S) -1- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -3- (3-fluoropyrrolidin-1-yl) propan-1-one (921);
(S) -1- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -3- (3-hydroxypyrrolidin-1-yl) propan-1-one (922);
1- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -3- (3-hydroxypyrrolidin-1-yl) propan-1-one (923);
3- (cyclohexyl (methyl) amino) -1- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) propan-1-one (924);
1- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -3- ((2-fluoroethyl) amino) propan-1-one (925);
1- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -3- (neopentylamino) propan-1-one (926);
4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidine-1-carboxylic acid azetidin-3-yl ester (927);
2-aminoethyl 4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidine-1-carboxylate (928);
4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidine-1-carboxylic acid (R) -pyrrolidin-3-yl ester (929);
4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidine-1-carboxylic acid piperidin-3-yl ester (930);
4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidine-1-carboxylic acid (S) -pyrrolidin-3-yl ester (931);
4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidine-1-carboxylic acid piperidin-3-ylmethyl ester (932);
4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidine-1-carboxylic acid (S) -pyrrolidin-2-ylmethyl ester (933);
3-aminopropyl 4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidine-1-carboxylate (934);
4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidine-1-carboxylic acid piperidin-4-yl ester (935);
4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidine-1-carboxylic acid piperidin-4-ylmethyl ester (936);
4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidine-1-carboxylic acid pyrrolidin-2-ylmethyl ester (937-938);
4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidine-1-carboxylic acid (R) -pyrrolidin-3-ylmethyl ester (939);
4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidine-1-carboxylic acid pyrrolidin-3-yl ester (940);
4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidine-1-carboxylic acid azetidin-3-ylmethyl ester (941);
(S) - (1-methylpyrrolidin-2-yl) methyl 4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidine-1-carboxylate (942);
2- (dimethylamino) ethyl 4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidine-1-carboxylate (943);
2- (1H-imidazol-1-yl) ethyl 4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidine-1-carboxylate (944);
4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidine-1-carboxylic acid 1-isopropylpyrrolidin-3-yl ester (945);
2- (1, 1-sulfur dioxide morpholino) ethyl 4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidine-1-carboxylate (946);
2- (piperidin-1-yl) ethyl 4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidine-1-carboxylate (947);
2- (pyrrolidin-1-yl) ethyl 4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidine-1-carboxylate (948);
2- (diethylamino) ethyl 4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidine-1-carboxylate (949);
4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidine-1-carboxylic acid (1- (2-methoxyethyl) pyrrolidin-3-yl) methyl ester (950);
2- (4-methylpiperazin-1-yl) ethyl 4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidine-1-carboxylate (951);
2-morpholinoethyl 4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidine-1-carboxylate (952);
4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidine-1-carboxylic acid (R) - (1-methylpyrrolidin-2-yl) methyl ester (953);
1-methylpyrrolidin-3-yl 4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidine-1-carboxylate (954);
4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidine-1-carboxylic acid 1- (2-methoxyethyl) azetidin-3-yl ester (955);
4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidine-1-carboxylic acid 1-propylazetidin-3-yl ester (956);
(4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) (4-methylpiperazin-1-yl) methanone (957);
(4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) (4- (2-hydroxyethyl) piperazin-1-yl) methanone (958);
n- (3-aminopropyl) -4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidine-1-carboxamide (959);
(4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) (octahydro-6H-pyrrolo [3, 4-b ] pyridin-6-yl) methanone ((960);
(R) -4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) -N- (pyrrolidin-3-yl) piperidine-1-carboxamide (961);
n- (2-aminoethyl) -4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidine-1-carboxamide (962);
4- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidine-1-carbonyl) -1-methylpiperazin-2-one (963);
4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) -N- (piperidin-3-yl) piperidine-1-carboxamide (964);
(4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) (4-propylpiperazin-1-yl) methanone (965);
4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) -N- (piperidin-2-ylmethyl) piperidine-1-carboxamide (966);
(3-aminoazetidin-1-yl) (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) methanone (967);
4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) -N- (pyrrolidin-3-yl) piperidine-1-carboxamide (968);
(4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) (4- (pyridin-4-yl) piperazin-1-yl) methanone (969);
4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) -N- (piperidin-4-ylmethyl) piperidine-1-carboxamide (970);
(S) -4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) -N- (pyrrolidin-3-yl) piperidine-1-carboxamide (971);
n- (2-aminoethyl) -4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) -N-methylpiperidine-1-carboxamide (972);
(4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) (4-isopropylpiperazin-1-yl) methanone (973);
4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) -N- (2- (pyrrolidin-1-yl) ethyl) piperidine-1-carboxamide (974);
4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) -N- ((1- (2-methoxyethyl) pyrrolidin-2-yl) methyl) piperidine-1-carboxamide (975);
4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) -N- (2- (4-methylpiperazin-1-yl) ethyl) piperidine-1-carboxamide (976);
4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) -N- ((1-methylpyrrolidin-2-yl) methyl) piperidine-1-carboxamide (977);
4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) -N- (2- (dimethylamino) ethyl) piperidine-1-carboxamide (978);
4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) -N- (2-morpholinoethyl) piperidine-1-carboxamide (979);
4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) -N- (2- (piperidin-1-yl) ethyl) piperidine-1-carboxamide (980);
6- (3-isopropyl-5- (1- (pyridin-2-yl) piperidin-4-yl) -1H-indol-2-yl) -7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (986);
1- (6- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) pyridin-3-yl) -N, N-dimethylmethylamine (987);
1- (2- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) pyridin-4-yl) -N, N-dimethylmethylamine (988); or
6- (3-isopropyl-5- (1- (pyrimidin-2-yl) piperidin-4-yl) -1H-indol-2-yl) -7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (989).
One embodiment provides a compound of formula (I-6) or a salt thereof, wherein R1is-CH (CH)3)2(ii) a m is 0; n is 0; and R is3As defined in the first or second aspect. The compounds of this embodiment have the structure of formula (I-6 a):
Figure BDA0001979596660000701
included in this embodiment are compounds wherein R is3Is- (CR)xRx)1-2C(O)NRyRyWherein each R isxIndependently is H or-CH3(ii) a And each RyIndependently is H or-CH3. Also included in this embodiment are those in which R3is-CH2C(O)NH2、-CH2C(O)NH(CH3) or-CH2C(O)N(CH3)2The compound of (1).
One embodiment provides a compound of formula (I) or a salt thereof, wherein the compound is selected from:
Figure BDA0001979596660000711
Included in this embodiment is 2- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) acetamide (15). Also included in this embodiment are one or more salts of 2- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) acetamide (15).
One embodiment provides a compound of formula (I) or a salt thereof, wherein the compound has the structure of formula (I-7):
Figure BDA0001979596660000712
wherein R is2Is F, Cl, -CN, -NH2、-CH2CH3、-CH(CH3)2、-CF3、C1-3Hydroxyalkyl, -CH2CN、-CH2OCH2CH3、-OCH2F、-OCH2CH3、-OCH2CH(CH3)2、-OCH2CH2OH、-OCH2CH2OC(O)CH3、-NH(CH2CH3)、-NH(CH2CF3)、-NH(CH2C(CH3)2OH)、-NHCH2(phenyl), -NHS (O)2(cyclopropyl), cyclopropyl, morpholinyl, methyl-piperazinyl, or dioxothiomorpholinyl; and R is1、R3、R4、R5M and n are defined in the first or second aspect. In this embodiment include those wherein R1is-CH (CH)3)2The compound of (1). Included in this embodiment are compounds wherein R is3Is H, C3-4Alkyl radical, C1-2Cyanoalkyl, -CH2C(CH3)2OH、-CH2C(O)N(CH3)2、-CH2C(O)NH(CH3)、-CH2C(O)NH2、-CH2CH2NHS(O)2CH3、-CH2CH2S(O)2CH3、-CH2CH2S(O)2NH2、-C(O)CH2CF3、-C(O)CH2CH2OH、-C(O)CH(CH3)OH、-C(O)CH2CH(CH3)OH、-C(O)CH2C(CH3)2OH、-C(O)CH2OCH3、-C(O)CH2CH2OCH3、-C(O)CH2NH(CH3)、-C(O)CH2N(CH3)2、-C(O)CH2N(CH3)(CH2CH3)、-C(O)CH2N(CH3)CH(CH3)2、-C(O)CH2CH2N(CH3)2or-L1-A；L1is-CH2-、-CH2CH2-、-C(O)-、-C(O)CH2-、-C(O)CH2CH2-、-C(O)CH2N(CH3)-、-CH2C (O) -; and A is cyclopropyl, dioxoisothiazolidinyl, dioxotetrahydrothiopyranyl, morpholinyl, oxetanyl, piperidinyl, pyrazinyl, pyrazolyl, pyrimidinyl, tetrahydrofuryl, tetrahydropyranyl, tetrazolyl, thiadiazolyl, thiazolyl or triazolyl, each of which is substituted by-L 2-RaSubstitution; l is2Is a bond; and R isaIs H, -CN, -CH3、-CF3or-OCH3. Also included in this embodiment are compounds wherein R is1is-CH (CH)3)2(ii) a m is 0; and n is 0.
One embodiment provides a compound of formula (I) or a salt thereof, wherein the compound is selected from:
8-ethyl-6- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridine (94);
8-isopropyl-6- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridine (95);
8- (ethoxymethyl) -6- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridine (99);
2- (6- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-8-yl) propan-2-ol (100);
1- (6- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-8-yl) ethan-1-ol (103);
6- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridine-8-carbonitrile (111);
8-fluoro-6- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridine (112);
(6- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-8-yl) methanol (113);
2- ((6- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-8-yl) oxy) ethan-1-ol (114);
2- (6- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-8-yl) ethan-1-ol (115);
acetic acid 2- ((6- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-8-yl) oxy) ethyl ester (116);
8-chloro-6- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridine (118);
6- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) -8- (trifluoromethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridine (128);
8-ethoxy-6- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridine (132);
8-isobutoxy-6- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridine (136);
4- (6- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-8-yl) morpholine (143);
n-ethyl-6- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-8-amine (144);
6- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) -N- (2, 2, 2-trifluoroethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-8-amine (145);
1- ((6- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-8-yl) amino) -2-methylpropan-2-ol (146);
n- (6- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-8-yl) cyclopropanesulfonamide (147);
4- (6- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-8-yl) thiomorpholine 1, 1-dioxide (148);
6- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) -8- (4-methylpiperazin-1-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridine (149);
8-cyclopropyl-6- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridine (151);
n-benzyl-6- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-8-amine (159);
8- (difluoromethoxy) -6- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridine (160);
2- (4- (2- (8- (ethoxymethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -N, N-dimethylacetamide (163);
2- (4- (2- (8-fluoro- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -N, N-dimethylacetamide (193);
8-fluoro-6- (3-isopropyl-5- (1- (2- (methylsulfonyl) ethyl) piperidin-4-yl) -1H-indol-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridine (194);
2- (4- (2- (8-fluoro- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) acetonitrile (195);
2- (4- (2- (8-fluoro- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) acetamide (196);
2- (4- (2- (8-fluoro- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -N-methylacetamide (197);
3- (4- (2- (8- (2-hydroxypropan-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) propionitrile (211);
2- (4- (2- (8- (2-hydroxypropan-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) acetonitrile (212);
2- (4- (2- (8- (2-hydroxypropan-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) acetamide (213);
2- (6- (3-isopropyl-5- (1- (2- (methylsulfonyl) ethyl) piperidin-4-yl) -1H-indol-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-8-yl) propan-2-ol (214);
n- (2- (4- (2- (8- (2-hydroxypropan-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) ethyl) methanesulfonamide (215);
2- (4- (2- (8- (2-hydroxypropan-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -N-methylacetamide (216);
2- (4- (2- (8- (2-hydroxypropan-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -N, N-dimethylacetamide (217);
2- (4- (2- (8- (2-hydroxypropan-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) ethane-1-sulfonamide (218);
n- (2- (4- (2- (8-cyano- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) ethyl) methanesulfonamide (220);
6- (5- (1- (2-hydroxy-2-methylpropyl) piperidin-4-yl) -3-isopropyl-1H-indol-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridine-8-carbonitrile (221);
6- (3-isopropyl-5- (1- (2- (methylsulfonyl) ethyl) piperidin-4-yl) -1H-indol-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridine-8-carbonitrile (222);
6- (5- (1- (cyanomethyl) piperidin-4-yl) -3-isopropyl-1H-indol-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridine-8-carbonitrile (223);
2- (4- (2- (8-cyano- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -N, N-dimethylacetamide (224);
2- (4- (2- (8- (1-hydroxyethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -N, N-dimethylacetamide (225);
2- (4- (2- (8- (cyanomethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -N, N-dimethylacetamide (228);
2- (4- (2- (8- (1-hydroxyethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) acetonitrile (229);
2- (4- (2- (8- (hydroxymethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -N, N-dimethylacetamide (231);
2- (4- (2- (8- (hydroxymethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) acetonitrile (232);
(6- (3-isopropyl-5- (1- (2- (methylsulfonyl) ethyl) piperidin-4-yl) -1H-indol-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-8-yl) methanol (233);
2- (4- (2- (8- (hydroxymethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -N-methylacetamide (234);
3- (4- (2- (8- (hydroxymethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) oxetane-3-carbonitrile (235);
2- (4- (2- (8- (2-hydroxyethoxy) - [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -N, N-dimethylacetamide (236);
2- (4- (3-isopropyl-2- (8- (trifluoromethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -N-methylacetamide (250);
2- (4- (3-isopropyl-2- (8- (trifluoromethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -N, N-dimethylacetamide (251);
1- (4- (3-isopropyl-2- (8- (trifluoromethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -2-methylpropan-2-ol (252);
2- (4- (3-isopropyl-2- (8- (trifluoromethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) acetonitrile (253);
6- (3-isopropyl-5- (1- (2- (methylsulfonyl) ethyl) piperidin-4-yl) -1H-indol-2-yl) -8- (trifluoromethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridine (254);
2- (4- (2- (8-ethoxy- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -N, N-dimethylacetamide (268);
2- (4- (2- (8-ethoxy- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -N-methylacetamide (269);
1- (4- (2- (8-ethoxy- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -2-methylpropan-2-ol (270);
2- (4- (2- (8-isobutoxy- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -N, N-dimethylacetamide (278);
2- (4- (2- (8-isobutoxy- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -N-methylacetamide (279);
2- (4- (2- (8-chloro- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -N, N-dimethylacetamide (280);
2- (4- (2- (8-chloro- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -N-methylacetamide (281);
1- (4- (2- (8-chloro- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -2-methylpropan-2-ol (282);
2- (4- (3-isopropyl-2- (8-morpholino- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -N-methylacetamide (291);
2- (4- (3-isopropyl-2- (8-morpholino- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -N, N-dimethylacetamide (292);
2- (4- (2- (8-ethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -N, N-dimethylacetamide (293);
2- (4- (2- (8-ethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -N-methylacetamide (294);
2- (4- (3-isopropyl-2- (8-isopropyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -N, N-dimethylacetamide (295);
2- (4- (3-isopropyl-2- (8-isopropyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -N-methylacetamide (296);
2- (4- (2- (8- (ethylamino) - [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -N-methylacetamide (297);
2- (4- (3-isopropyl-2- (8- ((2, 2, 2-trifluoroethyl) amino) - [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -N, N-dimethylacetamide (298);
2- (4- (3-isopropyl-2- (8- ((2, 2, 2-trifluoroethyl) amino) - [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -N-methylacetamide (299);
2- (4- (2- (8- ((2-hydroxy-2-methylpropyl) amino) - [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -N, N-dimethylacetamide (300);
2- (4- (2- (8- ((2-hydroxy-2-methylpropyl) amino) - [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -N-methylacetamide (301);
2- (4- (2- (8- (cyclopropanesulfonamido) - [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -N-methylacetamide (307);
2- (4- (2- (8- (1, 1-thiomorpholino) - [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -N-methylacetamide (308);
2- (4- (2- (8- (1, 1-thiomorpholino) - [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -N, N-dimethylacetamide (309);
6- (3-isopropyl-5- (1- (2- (methylsulfonyl) ethyl) piperidin-4-yl) -1H-indol-2-yl) -8- (4-methylpiperazin-1-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridine (310);
6- (3-isopropyl-5- (1- (2- (methylsulfonyl) ethyl) piperidin-4-yl) -1H-indol-2-yl) -8- (4-methylpiperazin-1-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridine (311);
2- (4- (2- (8-cyclopropyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -N-methylacetamide (319);
2- (4- (2- (8-cyclopropyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -N, N-dimethylacetamide (320);
8-cyclopropyl-6- (3-isopropyl-5- (1- (2- (methylsulfonyl) ethyl) piperidin-4-yl) -1H-indol-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridine (321);
1- (4- (2- (8-cyclopropyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -2-methylpropan-2-ol (322);
2- (4- (2- (8- (difluoromethoxy) - [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -N, N-dimethylacetamide (347);
2- (4- (2- (8- (benzylamino) - [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -N, N-dimethylacetamide (348);
8-fluoro-6- (3-isopropyl-5- (1- ((1-methyl-1H-1, 2, 3-triazol-4-yl) methyl) piperidin-4-yl) -1H-indol-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridine (468);
8-fluoro-6- (3-isopropyl-5- (1- (oxetan-3-yl) piperidin-4-yl) -1H-indol-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridine (469);
2- (6- (3-isopropyl-5- (1- ((2-methylpyrimidin-5-yl) methyl) piperidin-4-yl) -1H-indol-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-8-yl) propan-2-ol (490);
2- (6- (3-isopropyl-5- (1- ((1-methyl-1H-pyrazol-3-yl) methyl) piperidin-4-yl) -1H-indol-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-8-yl) propan-2-ol (491);
2- (6- (3-isopropyl-5- (1- (oxetan-3-yl) piperidin-4-yl) -1H-indol-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-8-yl) propan-2-ol (492);
2- (6- (3-isopropyl-5- (1- (tetrahydro-2H-pyran-4-yl) piperidin-4-yl) -1H-indol-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-8-yl) propan-2-ol (493);
2- (6- (3-isopropyl-5- (1- (pyrimidin-2-ylmethyl) piperidin-4-yl) -1H-indol-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-8-yl) propan-2-ol (494);
2- (6- (3-isopropyl-5- (1- ((1-methyl-1H-1, 2, 4-triazol-3-yl) methyl) piperidin-4-yl) -1H-indol-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-8-yl) propan-2-ol (495);
4- (4- (2- (8- (2-hydroxypropan-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) tetrahydro-2H-thiopyran 1, 1-dioxide (496);
2- (6- (5- (1- ((1H-1, 2, 3-triazol-4-yl) methyl) piperidin-4-yl) -3-isopropyl-1H-indol-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-8-yl) propan-2-ol (497);
2- (2- (4- (2- (8- (2-hydroxypropan-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) ethyl) isothiazolidine 1, 1-dioxide (498);
6- (3-isopropyl-5- (1- (tetrahydro-2H-pyran-4-yl) piperidin-4-yl) -1H-indol-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridine-8-carbonitrile (500);
6- (3-isopropyl-5- (1- (oxetan-3-yl) piperidin-4-yl) -1H-indol-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridine-8-carbonitrile (501);
1- (6- (3-isopropyl-5- (1- ((1-methyl-1H-1, 2, 3-triazol-4-yl) methyl) piperidin-4-yl) -1H-indol-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-8-yl) ethan-1-ol (502);
1- (6- (3-isopropyl-5- (1- (oxetan-3-yl) piperidin-4-yl) -1H-indol-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-8-yl) ethan-1-ol (503);
2- (6- (3-isopropyl-5- (1- (tetrahydro-2H-pyran-4-yl) piperidin-4-yl) -1H-indol-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-8-yl) acetonitrile (506);
(6- (3-isopropyl-5- (1- (oxetan-3-yl) piperidin-4-yl) -1H-indol-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-8-yl) methanol (510);
(6- (3-isopropyl-5- (1- ((1-methyl-1H-1, 2, 4-triazol-3-yl) methyl) piperidin-4-yl) -1H-indol-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-8-yl) methanol (511);
(6- (3-isopropyl-5- (1- ((2-methylpyrimidin-5-yl) methyl) piperidin-4-yl) -1H-indol-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-8-yl) methanol (512);
(6- (5- (1- ((1H-1, 2, 3-triazol-5-yl) methyl) piperidin-4-yl) -3-isopropyl-1H-indol-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-8-yl) methanol (513);
4- (4- (2- (8- (hydroxymethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) tetrahydro-2H-thiopyran 1, 1-dioxide (514);
(6- (3-isopropyl-5- (1- ((2-methoxypyrimidin-5-yl) methyl) piperidin-4-yl) -1H-indol-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-8-yl) methanol (515);
(6- (3-isopropyl-5- (1- ((1-methyl-1H-pyrazol-3-yl) methyl) piperidin-4-yl) -1H-indol-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-8-yl) methanol (516);
(6- (3-isopropyl-5- (1- (pyrimidin-5-ylmethyl) piperidin-4-yl) -1H-indol-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-8-yl) methanol (517);
(6- (5- (1- ((1, 2, 3-thiadiazol-4-yl) methyl) piperidin-4-yl) -3-isopropyl-1H-indol-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-8-yl) methanol (518);
(6- (3-isopropyl-5- (1- ((2-methylpyrimidin-4-yl) methyl) piperidin-4-yl) -1H-indol-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-8-yl) methanol (519);
(6- (3-isopropyl-5- (1- (pyrimidin-2-ylmethyl) piperidin-4-yl) -1H-indol-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-8-yl) methanol (520);
(6- (3-isopropyl-5- (1- (tetrahydro-2H-pyran-4-yl) piperidin-4-yl) -1H-indol-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-8-yl) methanol (521);
(6- (3-isopropyl-5- (1- ((2-methyl-2H-tetrazol-5-yl) methyl) piperidin-4-yl) -1H-indol-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-8-yl) methanol (522);
(6- (3-isopropyl-5- (1- ((1-methyl-1H-1, 2, 3-triazol-4-yl) methyl) piperidin-4-yl) -1H-indol-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-8-yl) methanol (523);
(6- (3-isopropyl-5- (1- ((5-methylpyrazin-2-yl) methyl) piperidin-4-yl) -1H-indol-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-8-yl) methanol (524);
2- (6- (3-isopropyl-5- (1- (oxetan-3-yl) piperidin-4-yl) -1H-indol-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-8-yl) ethan-1-ol (525);
2- (6- (3-isopropyl-5- (1- ((2-methylpyrimidin-5-yl) methyl) piperidin-4-yl) -1H-indol-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-8-yl) ethan-1-ol (526);
2- (6- (3-isopropyl-5- (1- ((1-methyl-1H-1, 2, 3-triazol-4-yl) methyl) piperidin-4-yl) -1H-indol-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-8-yl) ethan-1-ol (527);
acetic acid 2- ((6- (3-isopropyl-5- (1- (oxetan-3-yl) piperidin-4-yl) -1H-indol-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-8-yl) oxy) ethyl ester (528);
2- ((6- (3-isopropyl-5- (1- (oxetan-3-yl) piperidin-4-yl) -1H-indol-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-8-yl) oxy) ethan-1-ol (529-;
6- (3-isopropyl-5- (1- (oxetan-3-yl) piperidin-4-yl) -1H-indol-2-yl) -8- (trifluoromethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridine (549);
4- (4- (3-isopropyl-2- (8- (trifluoromethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) tetrahydro-2H-thiopyran 1, 1-dioxide (550);
6- (3-isopropyl-5- (1-isopropylpiperidin-4-yl) -1H-indol-2-yl) -8- (trifluoromethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridine (551);
6- (3-isopropyl-5- (1- (tetrahydro-2H-pyran-4-yl) piperidin-4-yl) -1H-indol-2-yl) -8- (trifluoromethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridine (552);
6- (5- (1-isobutylpiperidin-4-yl) -3-isopropyl-1H-indol-2-yl) -8- (trifluoromethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridine (553);
6- (3-isopropyl-5- (1- (tetrahydro-2H-pyran-3-yl) piperidin-4-yl) -1H-indol-2-yl) -8- (trifluoromethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridine (554);
6- (3-isopropyl-5- (1- ((3-methyloxetan-3-yl) methyl) piperidin-4-yl) -1H-indol-2-yl) -8- (trifluoromethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridine (555);
6- (3-isopropyl-5- (1- (tetrahydrofuran-3-yl) piperidin-4-yl) -1H-indol-2-yl) -8- (trifluoromethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridine (556-;
8-ethoxy-6- (3-isopropyl-5- (1- (tetrahydro-2H-pyran-4-yl) piperidin-4-yl) -1H-indol-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridine (571);
8-ethoxy-6- (3-isopropyl-5- (1- (oxetan-3-yl) piperidin-4-yl) -1H-indol-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridine (572);
4- (4- (2- (8-ethoxy- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) tetrahydro-2H-thiopyran 1, 1-dioxide (573);
4- (6- (3-isopropyl-5- (1- (oxetan-3-yl) piperidin-4-yl) -1H-indol-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-8-yl) morpholine (581);
8-ethyl-6- (5- (1-isobutylpiperidin-4-yl) -3-isopropyl-1H-indol-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridine (582);
8-ethyl-6- (3-isopropyl-5- (1- (oxetan-3-yl) piperidin-4-yl) -1H-indol-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridine (583);
6- (5- (1-isobutylpiperidin-4-yl) -3-isopropyl-1H-indol-2-yl) -8-isopropyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (584);
8-isopropyl-6- (3-isopropyl-5- (1- (oxetan-3-yl) piperidin-4-yl) -1H-indol-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridine (585);
6- (3-isopropyl-5- (1- (oxetan-3-yl) piperidin-4-yl) -1H-indol-2-yl) -N- (2, 2, 2-trifluoroethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-8-amine (586);
n- (6- (3-isopropyl-5- (1- (oxetan-3-yl) piperidin-4-yl) -1H-indol-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-8-yl) cyclopropanesulfonamide (590);
4- (6- (3-isopropyl-5- (1- (oxetan-3-yl) piperidin-4-yl) -1H-indol-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-8-yl) thiomorpholine 1, 1-dioxide (591);
6- (3-isopropyl-5- (1- (oxetan-3-yl) piperidin-4-yl) -1H-indol-2-yl) -8- (4-methylpiperazin-1-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridine (592);
8-cyclopropyl-6- (3-isopropyl-5- (1- (oxetan-3-yl) piperidin-4-yl) -1H-indol-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridine (593);
2- (dimethylamino) -1- (4- (2- (8-fluoro- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) ethan-1-one (640);
1- (4- (3-isopropyl-2- (8- (trifluoromethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -2- (methylamino) ethan-1-one (641);
2- (dimethylamino) -1- (4- (3-isopropyl-2- (8- (trifluoromethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) ethan-1-one (642);
1- (4- (3-isopropyl-2- (8- (trifluoromethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -2-methoxyethan-1-one (643);
1- (4- (3-isopropyl-2- (8- (trifluoromethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -3- (piperidin-1-yl) propan-1-one (644);
(4- (3-isopropyl-2- (8- (trifluoromethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) (tetrahydrofuran-2-yl) methanone (645);
1- (4- (3-isopropyl-2- (8- (trifluoromethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -3-methoxypropan-1-one (646);
3-hydroxy-1- (4- (3-isopropyl-2- (8- (trifluoromethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) propan-1-one (647);
3, 3, 3-trifluoro-1- (4- (3-isopropyl-2- (8- (trifluoromethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) propan-1-one (648);
3- (dimethylamino) -1- (4- (3-isopropyl-2- (8- (trifluoromethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) propan-1-one (649);
1- (4- (3-isopropyl-2- (8- (trifluoromethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -2- (2-methylthiazol-4-yl) ethan-1-one (650);
3-hydroxy-1- (4- (3-isopropyl-2- (8- (trifluoromethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -3-methylbutan-1-one (651);
2-hydroxy-1- (4- (3-isopropyl-2- (8- (trifluoromethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) propan-1-one (652);
(4- (3-isopropyl-2- (8- (trifluoromethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) (1- (trifluoromethyl) cyclopropyl) methanone (653);
(4- (3-isopropyl-2- (8- (trifluoromethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) (oxetan-3-yl) methanone (654);
1- (4- (3-isopropyl-2- (8- (trifluoromethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -2-morpholinoethan-1-one (655);
2- (dimethylamino) -1- (4- (2- (8-ethoxy- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) ethan-1-one (680);
1- (4- (2- (8-ethoxy- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -2- (methylamino) ethan-1-one (681);
2- (dimethylamino) -1- (4- (2- (8-isobutoxy- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) ethan-1-one (684);
(S) -1- (4- (2- (8-chloro- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -3-hydroxybutan-1-one (685);
1- (4- (2- (8-chloro- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -2- (dimethylamino) ethan-1-one (686);
2- (dimethylamino) -1- (4- (3-isopropyl-2- (8-morpholino- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) ethan-1-one (690);
2- (dimethylamino) -1- (4- (2- (8- (1, 1-thiomorpholino) - [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) ethan-1-one (691);
1- (4- (2- (8-cyclopropyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -2- (dimethylamino) ethan-1-one (696);
1- (4- (2- (8-cyclopropyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -2- (methylamino) ethan-1-one (697);
2- (isopropyl (methyl) amino) -1- (4- (3-isopropyl-2- (8- (trifluoromethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) ethan-1-one (777);
2- (ethyl (methyl) amino) -1- (4- (3-isopropyl-2- (8- (trifluoromethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) ethan-1-one (778);
2- (cyclopropyl (methyl) amino) -1- (4- (3-isopropyl-2- (8- (trifluoromethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) ethan-1-one (779);
2- (4- (2- (8- (2-hydroxypropan-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -1-morpholinoethan-1-one (850); and
2- (4- (2- (8-amino- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -N, N-dimethylacetamide (990).
One embodiment provides a compound of formula (I) or a salt thereof, wherein the compound has the structure of formula (I-8):
Figure BDA0001979596660000831
wherein each R2Independently of each other is F, Cl, -NH2、C1-2Alkyl, -CF3、-OCH3、-OCH2CH3、-OCHF2Cyclopropyl or morpholinyl; and R is1、R3、R4、R5M and n are defined in the first or second aspect. In this embodiment include those wherein R1is-CH2CH3、-CH(CH3)2or-CH2CHF2The compound of (1). Included in this embodiment are compounds wherein R is3Is H, -CH (CH)3)2、-CH2CH(CH3)2、-CH2C(CH3)2OH、-CH2C(O)NH(CH3)、-CH2C(O)N(CH3)2、-C(O)CH2CH(CH3)OH、-C(O)CH2C(CH3)2OH、-C(O)CH2NH(CH3)、-C(O)CH2N(CH3)2or-L1-A；L1is-CH2-, -C (O) -or-CH2C (O) -; and A is dioxotetrahydrothiopyranyl, dioxothiomorpholinyl, imidazolyl, morpholinyl, oxetanyl, pyrazolyl, pyrrolidinyl, tetrahydrofuranyl or tetrahydropyranyl, each of which is substituted by-L 2-RaAnd 0 to 1RbSubstitution; l is2Is a bond; raIs H, -OH, -CH3or-C (O) OC (CH)3)3(ii) a And R isbis-OH. Also included in this embodiment are compounds wherein R is1is-CH (CH)3)2(ii) a m is 0; and n is 0.
One embodiment provides a compound of formula (I) or a salt thereof, wherein the compound is selected from:
8-chloro-6- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) -2-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (96);
8-ethyl-6- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) -2-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (97);
6- (3-ethyl-5- (piperidin-4-yl) -1H-indol-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-2-amine (109);
6- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) -8-methyl-2- (trifluoromethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridine (120);
6- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) -2-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (122);
6- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) -2, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (124);
6- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) -2, 7-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (125);
8-fluoro-6- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) -2-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (126);
7-fluoro-6- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) -2-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (127);
6- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) -8-methoxy-2-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (133);
8- (difluoromethoxy) -6- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) -2-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (134);
8-ethoxy-6- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) -2-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (135);
8-chloro-6- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) -2, 7-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (138);
8-cyclopropyl-6- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) -2-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (141);
6- (3- (2, 2-difluoroethyl) -5- (piperidin-4-yl) -1H-indol-2-yl) -2-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (142);
4- (6- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) -2-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-8-yl) morpholine (150);
6- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) -2-methyl-8- (trifluoromethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridine (153);
6- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) -8-methoxy-2- (trifluoromethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridine (154);
6- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) -2, 5-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (155);
6- (3- (2, 2-difluoroethyl) -5- (piperidin-4-yl) -1H-indol-2-yl) -2, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (162);
2- (4- (3-isopropyl-2- (2-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -N-methylacetamide (237);
2- (4- (3-isopropyl-2- (2-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -N, N-dimethylacetamide (238);
1- (4- (3-isopropyl-2- (2-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -2-methylpropan-2-ol (239);
2- (4- (2- (2, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -N-methylacetamide (244);
2- (4- (2- (2, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -N, N-dimethylacetamide (245);
1- (4- (2- (2, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -2-methylpropan-2-ol (246);
2- (4- (2- (2, 7-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -N, N-dimethylacetamide (247);
2- (4- (2- (2, 7-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -N-methylacetamide (248);
1- (4- (2- (2, 7-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -2-methylpropan-2-ol (249);
2- (4- (3- (2, 2-difluoroethyl) -2- (2-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -N-methylacetamide (255);
2- (4- (3- (2, 2-difluoroethyl) -2- (2-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -N, N-dimethylacetamide (256);
2- (4- (2- (2, 5-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -N, N-dimethylacetamide (257);
2- (4- (2- (2, 5-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -N-methylacetamide (258);
2- (4- (3-isopropyl-2- (2-methyl-8- (trifluoromethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -N, N-dimethylacetamide (259);
2- (4- (2- (8-chloro-2-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -N, N-dimethylacetamide (260);
2- (4- (2- (8-chloro-2-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -N-methylacetamide (261);
1- (4- (2- (8-chloro-2-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -2-methylpropan-2-ol (262);
2- (4- (3-isopropyl-2- (8-methoxy-2-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -N, N-dimethylacetamide (271);
2- (4- (3-isopropyl-2- (8-methoxy-2-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -N-methylacetamide (272);
1- (4- (3-isopropyl-2- (8-methoxy-2-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -2-methylpropan-2-ol (273);
2- (4- (2- (8- (difluoromethoxy) -2-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -N, N-dimethylacetamide (274);
2- (4- (2- (8- (difluoromethoxy) -2-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -N-methylacetamide (275);
2- (4- (2- (8-ethoxy-2-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -N, N-dimethylacetamide (276);
2- (4- (2- (8-ethoxy-2-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -N-methylacetamide (277);
2- (4- (2- (8-ethyl-2-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -N, N-dimethylacetamide (283);
1- (4- (2- (8-ethyl-2-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -2-methylpropan-2-ol (284);
2- (4- (2- (8-ethyl-2-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -N-methylacetamide (285);
2- (4- (3-isopropyl-2- (8-methyl-2- (trifluoromethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -N, N-dimethylacetamide (312);
2- (4- (3-isopropyl-2- (8-methyl-2- (trifluoromethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -N-methylacetamide (313);
1- (4- (3-isopropyl-2- (8-methyl-2- (trifluoromethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -2-methylpropan-2-ol (314);
2- (4- (3-isopropyl-2- (2-methyl-8-morpholino- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -N, N-dimethylacetamide (315);
2- (4- (3-isopropyl-2- (2-methyl-8-morpholino- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -N-methylacetamide (316);
2- (4- (3-isopropyl-2- (8-methoxy-2- (trifluoromethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -N-methylacetamide (317);
2- (4- (3-isopropyl-2- (8-methoxy-2- (trifluoromethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -N, N-dimethylacetamide (318);
2- (4- (2- (8-cyclopropyl-2-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -N-methylacetamide (323);
1- (4- (2- (8-cyclopropyl-2-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -2-methylpropan-2-ol (324);
2- (4- (2- (8-cyclopropyl-2-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -N, N-dimethylacetamide (325);
2- (4- (3- (2, 2-difluoroethyl) -2- (2, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -N, N-dimethylacetamide (345);
2- (4- (3- (2, 2-difluoroethyl) -2- (2, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -N-methylacetamide (346);
2- (4- (3-isopropyl-2- (2-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -N-methylethyl-1-amine (531);
6- (3-isopropyl-5- (1- ((2-methyl-1H-imidazol-4-yl) methyl) piperidin-4-yl) -1H-indol-2-yl) -2-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (532);
6- (3-isopropyl-5- (1-isopropylpiperidin-4-yl) -1H-indol-2-yl) -2-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (533);
6- (3-isopropyl-5- (1- (oxetan-3-yl) piperidin-4-yl) -1H-indol-2-yl) -2-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (534);
6- (3-isopropyl-5- (1- (tetrahydro-2H-pyran-4-yl) piperidin-4-yl) -1H-indol-2-yl) -2-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (535);
6- (3-isopropyl-5- (1- (oxetan-3-yl) piperidin-4-yl) -1H-indol-2-yl) -2, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (542);
6- (3-isopropyl-5- (1- (tetrahydro-2H-pyran-4-yl) piperidin-4-yl) -1H-indol-2-yl) -2, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (543);
6- (5- (1-isobutylpiperidin-4-yl) -3-isopropyl-1H-indol-2-yl) -2, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (544);
4- (4- (2- (2, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) tetrahydro-2H-thiopyran 1, 1-dioxide (545);
6- (3-isopropyl-5- (1- (tetrahydro-2H-pyran-4-yl) piperidin-4-yl) -1H-indol-2-yl) -2, 7-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (546);
6- (3-isopropyl-5- (1- (oxetan-3-yl) piperidin-4-yl) -1H-indol-2-yl) -2, 7-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (547);
4- (4- (2- (2, 7-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) tetrahydro-2H-thiopyran 1, 1-dioxide (548);
6- (3-isopropyl-5- (1- (oxetan-3-yl) piperidin-4-yl) -1H-indol-2-yl) -2, 5-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (558);
6- (3-isopropyl-5- (1-isopropylpiperidin-4-yl) -1H-indol-2-yl) -2, 5-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (559);
6- (3-isopropyl-5- (1- ((1-methyl-1H-pyrazol-4-yl) methyl) piperidin-4-yl) -1H-indol-2-yl) -2, 5-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (560);
6- (3-isopropyl-5- (1- (oxetan-3-yl) piperidin-4-yl) -1H-indol-2-yl) -8-methoxy-2-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (574);
6- (3-isopropyl-5- (1- (tetrahydrofuran-3-yl) piperidin-4-yl) -1H-indol-2-yl) -8-methoxy-2-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (575-;
8-ethyl-6- (3-isopropyl-5- (1- (tetrahydro-2H-pyran-4-yl) piperidin-4-yl) -1H-indol-2-yl) -2-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (577);
8-ethyl-6- (3-isopropyl-5- (1- (oxetan-3-yl) piperidin-4-yl) -1H-indol-2-yl) -2-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (578);
8-cyclopropyl-6- (3-isopropyl-5- (1- (oxetan-3-yl) piperidin-4-yl) -1H-indol-2-yl) -2-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (594);
6- (3-isopropyl-5- (1-isopropylpiperidin-4-yl) -1H-indol-2-yl) -2, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (599);
2- (dimethylamino) -1- (4- (3-isopropyl-2- (2-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) ethan-1-one (612);
(R) -3-hydroxy-1- (4- (3-isopropyl-2- (2-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) butan-1-one (613);
3-hydroxy-1- (4- (3-isopropyl-2- (2-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -3-methylbutan-1-one (614);
((2S, 3R) -3-hydroxypyrrolidin-2-yl) (4- (3-isopropyl-2- (2-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) methanone (615);
((2S, 4R) -4-hydroxypyrrolidin-2-yl) (4- (3-isopropyl-2- (2-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) methanone (616);
(S) -3-hydroxy-1- (4- (3-isopropyl-2- (2-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) butan-1-one (617);
1- (4- (3-isopropyl-2- (2-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -2- (methylamino) ethan-1-one (618);
1- (4- (2- (2, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -2- (methylamino) ethan-1-one (629);
1- (4- (2- (2, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -2- (dimethylamino) ethan-1-one (630);
(S) -1- (4- (2- (2, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -3-hydroxybutan-1-one (631);
1- (4- (2- (2, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -3-hydroxy-3-methylbutan-1-one (632);
(R) -1- (4- (2- (2, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -3-hydroxybutan-1-one (633);
(2S, 3R) -2- (4- (2- (2, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidine-1-carbonyl) -3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (634);
(4- (2- (2, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) ((2S, 3R) -3-hydroxypyrrolidin-2-yl) methanone (635);
(4- (2- (2, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) ((2S, 4R) -4-hydroxypyrrolidin-2-yl) methanone (636);
(S) -1- (4- (2- (2, 7-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -3-hydroxybutan-1-one (637);
1- (4- (2- (2, 7-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -2- (dimethylamino) ethan-1-one (638);
1- (4- (2- (2, 7-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -2- (methylamino) ethan-1-one (639);
1- (4- (3- (2, 2-difluoroethyl) -2- (2-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -2- (dimethylamino) ethan-1-one (656);
(R) -1- (4- (3- (2, 2-difluoroethyl) -2- (2-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -3-hydroxybutan-1-one (657);
1- (4- (3- (2, 2-difluoroethyl) -2- (2-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -3-hydroxy-3-methylbutan-1-one (658);
1- (4- (3- (2, 2-difluoroethyl) -2- (2-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -2- (methylamino) ethan-1-one (659);
1- (4- (2- (2, 5-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -2- (dimethylamino) ethan-1-one (660);
1- (4- (2- (2, 5-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -2- (methylamino) ethan-1-one (661);
1- (4- (2- (8-chloro-2-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -2- (dimethylamino) ethan-1-one (662);
2- (dimethylamino) -1- (4- (3-isopropyl-2- (8-methoxy-2-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) ethan-1-one (682);
1- (4- (3-isopropyl-2- (8-methoxy-2-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -2- (methylamino) ethan-1-one (683);
2- (dimethylamino) -1- (4- (2- (8-ethyl-2-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) ethan-1-one (687);
1- (4- (2- (8-ethyl-2-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -2- (methylamino) ethan-1-one (688);
2- (dimethylamino) -1- (4- (3-isopropyl-2- (8-methyl-2- (trifluoromethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) ethan-1-one (692);
1- (4- (3-isopropyl-2- (8-methyl-2- (trifluoromethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -2- (methylamino) ethan-1-one (693);
(4- (3-isopropyl-2- (8-methyl-2- (trifluoromethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) (1-methylpiperidin-4-yl) methanone (694);
2- (dimethylamino) -1- (4- (3-isopropyl-2- (8-methoxy-2- (trifluoromethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) ethan-1-one (695);
1- (4- (2- (8-cyclopropyl-2-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -2- (dimethylamino) ethan-1-one (698);
1- (4- (3- (2, 2-difluoroethyl) -2- (2, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -2- (dimethylamino) ethan-1-one (708);
(S) -1- (4- (3- (2, 2-difluoroethyl) -2- (2, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -3-hydroxybutan-1-one (709);
1- (4- (3- (2, 2-difluoroethyl) -2- (2, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -3-hydroxy-3-methylbutan-1-one (710);
1- (4- (3- (2, 2-difluoroethyl) -2- (2, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -2- (methylamino) ethan-1-one (711);
2- (4- (2- (2, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -1- (pyrrolidin-1-yl) ethan-1-one (851);
2- (4- (2- (2, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -1-morpholinoethan-1-one (852); and
2- (4- (2- (2, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -1- (1, 1-sulfur dioxide morpholino) ethan-1-one (853).
One embodiment provides a compound of formula (I) or a salt thereof, wherein the compound has the structure of formula (I-9):
Figure BDA0001979596660000911
wherein R is2Is F, Cl, -CH2CH3、-CF3、-OCH3、-CH2OH、-CH2OCH3Or cyclopropyl; and R is1、R3、R4、R5M and n are defined in the first or second aspect. In this embodiment include those wherein R1is-CH (CH)3)2The compound of (1). Included in this embodiment are compounds wherein R is3Is H, -CH (CH)3)2、-CH2CH(CH3)2、-CH2C(CH3)2OH、-CH2C(O)NH(CH3)、-CH2C(O)N(CH3)2、-C(O)CH2CH(CH3)OH、-C(O)CH2C(CH3)2OH、-C(O)CH2NH(CH3)、-C(O)CH2N(CH3)2or-L1-A；L1is-CH2-、-CH2C(O)NHCH2-or-CH2C (O) -; and A is azetidinyl, dioxothiomorpholinyl, morpholinyl, oxetanyl, tetrahydropyranyl or triazolyl, each of which is-L2-RaSubstitution; l is2Is a bond; raIs H or-CH3. Also included in this embodiment are compounds wherein R is1is-CH (CH) 3)2(ii) a m is 0; and n is 0.
One embodiment provides a compound of formula (I) or a salt thereof, wherein the compound is selected from:
4- (2- (8-ethyl-7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidine-1-carboxylic acid tert-butyl ester (98);
6- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) -8- (methoxymethyl) -7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (101);
8-fluoro-6- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) -7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (102);
(6- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) -7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-8-yl) methanol (104);
8-fluoro-6- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) -7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (106);
8-fluoro-6- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) -7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (107);
8-chloro-6- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) -7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (119);
6- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) -8-methoxy-7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (140);
8-cyclopropyl-6- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) -7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (152);
2- (4- (3-isopropyl-2- (8- (methoxymethyl) -7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -N, N-dimethylacetamide (219);
2- (4- (2- (8- (hydroxymethyl) -7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -N, N-dimethylacetamide (226);
2- (4- (2- (8- (hydroxymethyl) -7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) acetonitrile (227);
2- (4- (2- (8-chloro-7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -N, N-dimethylacetamide (286);
1- (4- (2- (8-chloro-7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -2-methylpropan-2-ol (287);
2- (4- (2- (8-chloro-7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -N-methylacetamide (288);
2- (4- (2- (8-chloro-7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -N-methylacetamide (289);
8-chloro-6- (3-isopropyl-5- (1- (2- (methylsulfonyl) ethyl) piperidin-4-yl) -1H-indol-2-yl) -7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (290);
2- (4- (2- (8-ethyl-7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -N, N-dimethylacetamide (302);
2- (4- (3-isopropyl-2- (8-methoxy-7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -N-methylacetamide (303);
2- (4- (3-isopropyl-2- (8-methoxy-7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -N, N-dimethylacetamide (304);
1- (4- (3-isopropyl-2- (8-methoxy-7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -2-methylpropan-2-ol (305);
6- (3-isopropyl-5- (1- (2- (methylsulfonyl) ethyl) piperidin-4-yl) -1H-indol-2-yl) -8-methoxy-7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (306);
2- (4- (2- (8-cyclopropyl-7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -N-methylacetamide (326);
2- (4- (2- (8-cyclopropyl-7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -N, N-dimethylacetamide (327);
1- (4- (2- (8-cyclopropyl-7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -2-methylpropan-2-ol (328);
6- (3-isopropyl-5- (1- (oxetan-3-yl) piperidin-4-yl) -1H-indol-2-yl) -8- (methoxymethyl) -7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (499);
(6- (3-isopropyl-5- (1- (oxetan-3-yl) piperidin-4-yl) -1H-indol-2-yl) -7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-8-yl) methanol (504);
(6- (5- (1- ((1H-1, 2, 3-triazol-4-yl) methyl) piperidin-4-yl) -3-isopropyl-1H-indol-2-yl) -7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-8-yl) methanol (505);
8-fluoro-6- (3-isopropyl-5- (1- (oxetan-3-yl) piperidin-4-yl) -1H-indol-2-yl) -7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (507);
8-chloro-6- (3-isopropyl-5- (1- (tetrahydro-2H-pyran-4-yl) piperidin-4-yl) -1H-indol-2-yl) -7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (579);
8-chloro-6- (3-isopropyl-5- (1- (oxetan-3-yl) piperidin-4-yl) -1H-indol-2-yl) -7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (580);
8-ethyl-6- (3-isopropyl-5- (1- (oxetan-3-yl) piperidin-4-yl) -1H-indol-2-yl) -7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (587);
6- (3-isopropyl-5- (1- (oxetan-3-yl) piperidin-4-yl) -1H-indol-2-yl) -8-methoxy-7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (588);
6- (3-isopropyl-5- (1- ((3-methyloxetan-3-yl) methyl) piperidin-4-yl) -1H-indol-2-yl) -8-methoxy-7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (589);
8-cyclopropyl-6- (3-isopropyl-5- (1- (oxetan-3-yl) piperidin-4-yl) -1H-indol-2-yl) -7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (595);
1- (4- (2- (8-chloro-7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -2- (dimethylamino) ethan-1-one (689);
1- (4- (2- (8-cyclopropyl-7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -2- (dimethylamino) ethan-1-one (699);
1- (4- (2- (8-cyclopropyl-7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -2- (methylamino) ethan-1-one (700);
2- (4- (3-isopropyl-2- (8-methoxy-7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -N- ((3-methyloxetan-3-yl) methyl) acetamide (876);
2- (4- (3-isopropyl-2- (8-methoxy-7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -N- (3-methyloxetan-3-yl) acetamide (877);
1- (azetidin-1-yl) -2- (4- (3-isopropyl-2- (8-methoxy-7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) ethan-1-one (878);
n-ethyl-2- (4- (3-isopropyl-2- (8-methoxy-7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -N-methylacetamide (879);
1- (1, 1-thiomorpholino) -2- (4- (3-isopropyl-2- (8-methoxy-7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) ethan-1-one (880); and
2- (4- (3-isopropyl-2- (8-methoxy-7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -1-morpholinoethan-1-one (881).
One embodiment provides a compound of formula (I) or a salt thereof, wherein the compound has the structure of formula (I-10):
Figure BDA0001979596660000951
wherein R is2is-CH3、-OCH3or-CH2OH; and R is1、R3、R4、R5M and n are defined in the first or second aspect. In this embodiment include those wherein R1is-CH (CH)3)2The compound of (1). In this embodiment include those wherein R3Is H, -CH2CN、-CH2C(O)NH2、-CH2C(O)N(CH3)2、-CH2(triazolyl) or oxetanyl compounds. Also included in this embodiment are compounds wherein R is1is-CH (CH)3)2(ii) a m is 0; and n is 0.
One embodiment provides a compound of formula (I) or a salt thereof, wherein the compound is selected from:
(6- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-7-yl) methanol (108);
6- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) -7-methoxy- [1, 2, 4] triazolo [1, 5-a ] pyridine (131);
2- (4- (3-isopropyl-2- (7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) acetamide (192);
2- (4- (2- (7- (hydroxymethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) acetonitrile (230);
2- (4- (3-isopropyl-2- (7-methoxy- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -N, N-dimethylacetamide (267);
(6- (3-isopropyl-5- (1- (oxetan-3-yl) piperidin-4-yl) -1H-indol-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-7-yl) methanol (508); and
(6- (3-isopropyl-5- (1- ((1-methyl-1H-1, 2, 3-triazol-4-yl) methyl) piperidin-4-yl) -1H-indol-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-7-yl) methanol (509).
One embodiment provides a compound of formula (I) or a salt thereof, wherein the compound has the structure of formula (I-11):
Figure BDA0001979596660000961
Wherein R is1、R3、R4、R5M and n are defined in the first or second aspect. In this embodiment include those wherein R1is-CH (CH)3)2The compound of (1). Included in this embodiment are compounds wherein R is3is-CH2CN、-CH2C(O)N(CH3)2、-CH2CH2S(O)2CH3、-CH2(methyltriazolyl), -C (O) CH2N(CH3)2Dioxotetrahydrothiopyranyl, oxetanyl or tetrahydropyranyl. Also included in this embodiment are compounds wherein R is1is-CH (CH)3)2(ii) a m is 0; and n is 0.
One embodiment provides a compound of formula (I) or a salt thereof, wherein the compound is selected from:
2- (4- (2- (5, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -N, N-dimethylacetamide (207);
6- (3-isopropyl-5- (1- ((1-methyl-1H-1, 2, 4-triazol-3-yl) methyl) piperidin-4-yl) -1H-indol-2-yl) -5, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (208);
6- (3-isopropyl-5- (1- (2- (methylsulfonyl) ethyl) piperidin-4-yl) -1H-indol-2-yl) -5, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (209);
2- (4- (2- (5, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) acetonitrile (210);
6- (3-isopropyl-5- (1- (oxetan-3-yl) piperidin-4-yl) -1H-indol-2-yl) -5, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (487);
6- (3-isopropyl-5- (1- (tetrahydro-2H-pyran-4-yl) piperidin-4-yl) -1H-indol-2-yl) -5, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (488);
4- (4- (2- (5, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) tetrahydro-2H-thiopyran 1, 1-dioxide (489); and
1- (4- (2- (5, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -2- (dimethylamino) ethan-1-one (611).
One embodiment provides a compound of formula (I) or a salt thereof, wherein the compound is selected from:
2- (6- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-8-yl) acetonitrile (105); and
6- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) -5-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (123).
One embodiment provides a compound of formula (I) or a salt thereof, wherein the compound is selected from:
6- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridine (1);
6- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) -8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine hydrochloride (2);
6- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) -7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (3);
6- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) -7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (4);
6- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) -8-methoxy- [1, 2, 4] triazolo [1, 5-a ] pyridine (5);
6- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) -8- (methoxymethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridine (6);
2- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -N-methylacetamide (7);
2- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) acetonitrile (8);
3- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) propionitrile (9);
6- (5- (1-butylpiperidin-4-yl) -3-isopropyl-1H-indol-2-yl) -8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (10);
2- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) acetamide (11);
1- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -2-methylpropan-2-ol (12);
2- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) acetonitrile (13);
3- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) propionitrile (14);
2- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) acetamide (15);
2- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -N-methylacetamide (16);
1- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -2-methylpropan-2-ol (17);
6- (3-isopropyl-5- (1- (2- (methylsulfonyl) ethyl) piperidin-4-yl) -1H-indol-2-yl) -7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (18);
2- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) ethane-1-sulfonamide (19);
4- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) tetrahydro-2H-thiopyran 1, 1-dioxide (20);
2- (4- (3-isopropyl-2- (8-methoxy- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) acetonitrile (21);
2- (4- (3-isopropyl-2- (8-methoxy- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) acetamide (22);
2- (4- (3-isopropyl-2- (8-methoxy- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -N-methylacetamide (23);
1- (4- (3-isopropyl-2- (8-methoxy- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -2-methylpropan-2-ol (24);
2- (4- (3-isopropyl-2- (8-methoxy- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -N, N-dimethylacetamide (25);
6- (3-isopropyl-5- (1- (oxetan-3-yl) piperidin-4-yl) -1H-indol-2-yl) -8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (26);
6- (3-isopropyl-5- (1-isopropylpiperidin-4-yl) -1H-indol-2-yl) -8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (27);
6- (3-isopropyl-5- (1-propylpiperidin-4-yl) -1H-indol-2-yl) -8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (28);
6- (5- (1-isobutylpiperidin-4-yl) -3-isopropyl-1H-indol-2-yl) -8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (29);
6- (5- (1- ((1H-pyrazol-5-yl) methyl) piperidin-4-yl) -3-isopropyl-1H-indol-2-yl) -8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (30);
4- ((4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) methyl) oxazole (31);
6- (5- (1- ((1H-1, 2, 3-triazol-4-yl) methyl) piperidin-4-yl) -3-isopropyl-1H-indol-2-yl) -8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (32);
6- (5- (1- ((4H-1, 2, 4-triazol-3-yl) methyl) piperidin-4-yl) -3-isopropyl-1H-indol-2-yl) -8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (33);
6- (5- (1- ((1H-tetrazol-5-yl) methyl) piperidin-4-yl) -3-isopropyl-1H-indol-2-yl) -8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (34);
6- (3-isopropyl-5- (1- (tetrahydro-2H-pyran-4-yl) piperidin-4-yl) -1H-indol-2-yl) -8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (35);
2- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -N, N-dimethylacetamide (36);
4- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) tetrahydro-2H-thiopyran 1, 1-dioxide (37);
6- (3-isopropyl-5- (1- (oxetan-3-yl) piperidin-4-yl) -1H-indol-2-yl) -7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (38);
6- (5- (1- ((1H-1, 2, 3-triazol-5-yl) methyl) piperidin-4-yl) -3-isopropyl-1H-indol-2-yl) -7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (39);
6- (3-isopropyl-5- (1- (tetrahydro-2H-pyran-4-yl) piperidin-4-yl) -1H-indol-2-yl) -7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (40);
2- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -N, N-dimethylacetamide (41);
6- (3-isopropyl-5- (1- ((1-methyl-1H-1, 2, 3-triazol-4-yl) methyl) piperidin-4-yl) -1H-indol-2-yl) -7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (42);
6- (3-isopropyl-5- (1- ((1-methyl-1H-1, 2, 4-triazol-3-yl) methyl) piperidin-4-yl) -1H-indol-2-yl) -7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (43);
6- (3-isopropyl-5- (1- (oxetan-3-yl) piperidin-4-yl) -1H-indol-2-yl) -8-methoxy- [1, 2, 4] triazolo [1, 5-a ] pyridine (44);
6- (3-isopropyl-5- (1- (tetrahydro-2H-pyran-4-yl) piperidin-4-yl) -1H-indol-2-yl) -8-methoxy- [1, 2, 4] triazolo [1, 5-a ] pyridine (45);
2- (dimethylamino) -1- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) ethan-1-one (46);
1- (4- (2- ([1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -2- (methylamino) ethan-1-one (47);
1- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) ethan-1-one (48);
3- (4- (3-isopropyl-2- (7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -3-oxopropanenitrile (49);
1- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -2- (methylamino) ethan-1-one (50);
1- (4- (2- ([1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -2- (dimethylamino) ethan-1-one (51);
1- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -2-methoxyethan-1-one (52);
(S) -1- (4- (2- ([1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -3-hydroxybutan-1-one (53);
4- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -4-oxobutanenitrile (54);
(4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) (1-methylcyclopropyl) methanone (55);
(S) -azetidin-2-yl (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) methanone (56);
2- (dimethylamino) -1- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) ethan-1-one (57);
(S) -1- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -2- (methylamino) propan-1-one (58);
(R) -1- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -2- (methylamino) propan-1-one (59);
(S) -3-hydroxy-1- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) butan-1-one (60);
1- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -3-methoxypropan-1-one (61);
1- (4- (3-isopropyl-2- (8-methoxy- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -2- (methylamino) ethan-1-one (62);
1- (4- (3-isopropyl-2- (8-methoxy- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -2-methoxyethan-1-one (63);
(4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) (3-methyloxetan-3-yl) methanone (64);
2-ethyl-1- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) butan-1-one (65);
1- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -2- (dimethylamino) ethan-1-one (66);
2- (dimethylamino) -1- (4- (3-isopropyl-2- (8-methoxy- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) ethan-1-one (67);
1- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -2-morpholinoethan-1-one (68);
2- (tert-butylamino) -1- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) ethan-1-one (69);
1- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -2- (isopropylamino) ethan-1-one (70);
1- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -2- ((2-methoxyethyl) amino) ethan-1-one (71);
1- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -2- (propylamino) ethan-1-one (72);
2- (isopropyl (methyl) amino) -1- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) ethan-1-one (73);
1- (1, 1-dioxido-1, 2, 4-thiadiazinan-4-yl) -2- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) ethan-1-one (74);
n-cyclopropyl-2- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) acetamide (75);
n-ethyl-2- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -N-methylacetamide (76);
(S) -1- (3-hydroxypiperidin-1-yl) -2- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) ethan-1-one (77);
N-cyclobutyl-2- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) acetamide (78);
2- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -1- (2-oxa-6-azaspiro [3.3] hept-6-yl) ethan-1-one (79);
n, N-diethyl-2- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) acetamide (80);
2- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -n-propylacetamide (81);
(R) -1- (3-hydroxypiperidin-1-yl) -2- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) ethan-1-one (82);
(S) -1- (3-hydroxypyrrolidin-1-yl) -2- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) ethan-1-one (83);
(R) -1- (3-hydroxypyrrolidin-1-yl) -2- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) ethan-1-one (84);
2- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -1- (4- (2-methoxyethyl) piperazin-1-yl) ethan-1-one (85);
1- (azetidin-1-yl) -2- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) ethan-1-one (86);
n-isopropyl-2- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) acetamide (87);
2- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -1-morpholinoethan-1-one (88);
2- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -1- (piperidin-1-yl) ethan-1-one (89);
2- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -1- (pyrrolidin-1-yl) ethan-1-one (90);
1- (1, 1-thiomorpholino) -2- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) ethan-1-one (91);
2- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -N- (3-methyloxetan-3-yl) acetamide (92); and
n-cyclopropyl-2- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -N-methylacetamide (93).
One embodiment provides a process of formula (I)A compound or a salt thereof, wherein R1is-CH (CH)3)2(ii) a Each R2Independently is-CH3or-OCH3；R3Is- (CR)xRx)1-2C(O)NRyRy(ii) a m is 0; n is 0; p is 1 or 2; each RxIndependently is H or-CH3(ii) a And each RyIndependently is H or-CH3. In this embodiment include those wherein R3is-CH2C(O)NRyRyThe compound of (1). Also included in this embodiment are compounds having the structure of formula (I-4b) or formula (I-6b), wherein each RyIs H or-CH3：
Figure BDA0001979596660001031
Also included in this embodiment are those wherein R3is-CH2C(O)NH2or-CH2C(O)N(CH3)2The compound of (1).
This application is capable of implementation in other specific forms without departing from its spirit or essential attributes. This application is intended to cover all combinations of aspects and/or embodiments of the present application described herein. It should be understood that any and all embodiments herein may be combined with any one or more other embodiments to describe additional embodiments. It should also be understood that each individual element of an embodiment may be combined with any and all other elements from any embodiment to describe additional embodiments.
Definition of
The features and advantages of the present application will become more readily apparent to those of ordinary skill in the art after reviewing the following detailed description. It is to be understood that certain features of the application, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the application that are, for brevity, described in the context of a single embodiment, may also be provided in combination in a subcombination. The exemplary or preferred embodiments of this application are intended to be illustrative, not limiting.
Where reference is made to the singular, the plural reference may also be included, unless the application specifically states otherwise. For example, "a" or "an" may refer to one or more than one.
The phrase "compound" as used herein refers to at least one compound. For example, compounds of formula (I) include compounds of formula (I) and two or more compounds of formula (I).
Unless otherwise specified, any heteroatom whose valency is not satisfied is presumed to have a hydrogen atom sufficient to satisfy the valency.
The definitions described herein take precedence over definitions described in any patent, patent application, and/or patent application publication incorporated by reference.
The following sets forth definitions of various terms used to describe the present application. These definitions apply to the terms used throughout the specification (unless they are otherwise limited in specific instances) individually or as part of a larger group.
Throughout the specification, the skilled artisan may select groups and substituents thereof to provide stable moieties and compounds.
According to the conventional usage in the field,
Figure BDA0001979596660001041
the following bonds are used in the structural formulae herein to describe the point of attachment of a moiety or substituent to the parent nucleus or backbone structure.
The terms "halo" and "halogen" as used herein refer to F, Cl, Br and I.
The term "cyano" refers to the group-CN.
The term "amino" refers to the group-NH2。
The term "oxo" refers to the group ═ O.
The term "alkyl" as used herein refers to branched and straight chain saturated aliphatic hydrocarbon groups containing, for example, 1 to 12 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, sec-butyl and tert-butyl), and pentyl(e.g., n-pentyl, isopentyl, and neopentyl), n-hexyl, 2-methylpentyl, 2-ethylbutyl, 3-methylpentyl, and 4-methylpentyl. When a number appears in a subscript position following the symbol "C," the subscript more specifically defines the number of carbon atoms that a particular group may contain. For example, "C1-C6Alkyl "denotes straight and branched chain alkyl groups having one to six carbon atoms.
The term "fluoroalkyl" as used herein is intended to include both branched and straight chain saturated aliphatic hydrocarbon groups substituted with one or more fluorine atoms. For example, "C1-4Fluoroalkyl "is intended to include C substituted with one or more fluorine atoms 1、C2、C3And C4An alkyl group. Representative examples of fluoroalkyl groups include, but are not limited to, -CF3and-CH2CF3。
The term "chloroalkyl" as used herein is intended to include both branched and straight chain saturated aliphatic hydrocarbon groups substituted with one or more chlorine atoms. For example, "C1-4Chloroalkyl "is intended to include C substituted with one or more chlorine atoms1、C2、C3And C4An alkyl group. Representative examples of chloroalkyl groups include, but are not limited to, -CCl3and-CH2CCl3。
The term "cyanoalkyl" includes branched and straight chain saturated alkyl groups substituted with one or more cyano groups. For example, "cyanoalkyl" includes-CH2CN、-CH2CH2CN and C1-4Cyanoalkyl group.
The term "aminoalkyl" includes branched and straight chain saturated alkyl groups substituted with one or more amino groups. For example, "aminoalkyl" includes-CH2NH2、-CH2CH2NH2And C1-4An aminoalkyl group.
The term "hydroxyalkyl" includes branched and straight chain saturated alkyl groups substituted with one or more hydroxyl groups. For example, "hydroxyalkyl" includes-CH2OH、-CH2CH2OH and C1-4A hydroxyalkyl group.
The term "hydroxy-fluoroalkyl" includes one or more hydroxy groupsAnd branched and straight-chain saturated alkyl groups substituted with one or more fluorine atoms. For example, "hydroxy-fluoroalkyl" includes-CHFCH2OH、-CH2CHFC(CH3)2OH and C1-4A hydroxy-fluoroalkyl group.
The term "cycloalkyl" as used herein refers to a group derived from a non-aromatic monocyclic or polycyclic hydrocarbon molecule by the removal of one hydrogen atom from a saturated ring carbon atom. Representative examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclopentyl, and cyclohexyl. When a number appears in a subscript position following the symbol "C," the subscript more specifically defines the number of carbon atoms that a particular cycloalkyl group may contain. For example, "C 3-C6Cycloalkyl "means a cycloalkyl group having three to six carbon atoms.
The term "alkoxy," as used herein, refers to an alkyl group such as methoxy (-OCH) attached to the parent molecular moiety through an oxygen atom3). For example, "C1-3Alkoxy "means an alkoxy group having one to three carbon atoms.
The terms "fluoroalkoxy" and "-O (fluoroalkyl)" represent fluoroalkyl groups as defined above linked via an oxygen linkage (-O-). For example, "C1-4Fluoroalkoxy "is intended to include C1、C2、C3And C4A fluoroalkoxy group.
The term "alkoxyalkoxy," as used herein, refers to an alkoxy group attached via its oxygen atom to a carbon atom in a second alkoxy group attached to the parent molecular moiety through an oxygen atom, e.g., methoxymethoxy (-OCH)2OCH3). For example, "C2-4Alkoxyalkoxy "denotes alkoxyalkoxy having two to four carbon atoms such as-OCH2OCH3、-OCH2CH2OCH3、-OCH2OCH2CH3and-OCH2CH2OCH2CH3。
The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
The compounds of formula (I) may be provided in amorphous solid or crystalline solid form. Lyophilization may be employed to provide the compound of formula (I) in amorphous solid form.
It is also understood that solvates (e.g., hydrates) of the compounds of formula (I) are also within the scope of the present application. The term "solvate" means a physical association of a compound of formula (I) with one or more solvent molecules (organic or inorganic). The physical association includes hydrogen bonding. In some cases, the solvate will be able to separate, for example when one or more solvent molecules are introduced into the crystal lattice of the crystalline solid. "solvates" encompasses both solution phase and isolatable solvates. Exemplary solvates include hydrates, ethanolates, methanolates, isopropanol solvates, acetonitrile solvates, and ethyl acetate solvates. Solvation methods are known in the art.
Various forms of prodrugs are known in the art and are described in:
a) the Practice of Medicinal Chemistry, Camile G.Wermuth et al, Ch 31, (Academic Press, 1996);
b) design of produgs, edited by h.bundgaard, (Elsevier, 1985);
c) a Textbook of Drug Design and Development, P.Krogsgaard-Larson and H.Bundgaard eds, Chapter 5, pp 113-191 (Harwood Academic Publishers, 1991); and
d) Hydrolysis in Drug and Prodrug Metabolism, Bernard Testa and Joachim M.Mayer, (Wiley-VCH, 2003).
In addition, the compound of formula (I) may be isolated and purified after its preparation to yield a composition containing the compound of formula (I) in an amount equal to or greater than 99% by weight ("substantially pure"), which is then used or formulated as described herein. Such "substantially pure" compounds of formula (I) also form part of the present application.
"stable compound" and "stable structure" are intended to mean that the compound is sufficiently stable to survive isolation to a useful degree of purity from a reaction mixture and formulation into an effective therapeutic agent. The present application is intended to include stable compounds.
"therapeutically effective amount" is intended to include individual amounts of a compound of the present application or combined amounts of a plurality of claimed compounds or combined amounts of a compound of the present application and other active ingredients effective as inhibitors of TLR7/8/9 or effective in the treatment or prevention of autoimmune and/or inflammatory disorders such as SLE, IBD, Multiple Sclerosis (MS), sjogren's syndrome and rheumatoid arthritis.
As used herein, "treatment" includes the treatment of a condition in a mammal, particularly a human, and includes: (a) preventing the occurrence of said disorder in a mammal, particularly when such mammal is susceptible to said disorder but has not yet been diagnosed with it; (b) inhibiting, i.e. arresting the development of, said condition; and/or (c) alleviating, i.e. allowing regression of, the condition.
The compounds of the present application are intended to include all isotopes of atoms occurring in the compounds of the present application. Isotopes include those atoms having the same number of atoms but different mass numbers. As a general example, but not limited thereto, isotopes of hydrogen include deuterium (D) and tritium (T). Isotopes of carbon include13C and14C. isotopically-labeled compounds of the present application can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein using an appropriate isotopically-labeled reagent in place of the unlabeled reagent otherwise used. For example, methyl (-CH)3) Also includes deuterated methyl groups such as-CD3。
Practicality of use
The human immune system has evolved to defend the body against microorganisms, viruses, and parasites that can cause infection, disease, or death. The complex regulatory mechanisms ensure that various cellular components of the immune system target foreign substances or organisms without causing permanent or significant damage to the individual. While triggering events are not well understood at this time, in autoimmune disorders, the immune system directs its inflammatory response to target the organs of the affected individual. Different autoimmune diseases are often characterized by the effects of a primary or primary target organ or tissue; such as the joints in the case of rheumatoid arthritis, the thyroid in the case of hashimoto's thyroiditis, the central nervous system in the case of multiple sclerosis, the pancreas in the case of type I diabetes and the intestine in the case of inflammatory bowel disease.
The compounds of the present application inhibit signaling via Toll-like receptors 7 or 8 or 9(TLR7, TLR8, TLR9) or combinations thereof. Thus, the compounds of formula (I) have utility in the treatment of disorders associated with the inhibition of signaling through one or more of TLR7, TLR8 or TLR 9. Such disorders include TLR7, TLR8, or TLR9 receptor-related diseases in which cytokine levels are modulated due to intracellular signaling.
The term "treatment" as used herein includes the treatment of a condition in a mammal, particularly a human, and includes: (a) preventing or delaying the onset of said disorder in a mammal, particularly when such mammal is susceptible to said disorder but has not yet been diagnosed with it; (b) inhibiting, i.e. arresting the development of, said condition; and/or (c) effecting a complete or partial reduction of the symptoms or condition and/or alleviating, ameliorating, reducing or curing the disease or disorder and/or the symptoms thereof.
Compounds of formula (I) are useful in the treatment of TLR7, TLR8 or TLR9 family receptor related diseases including but not limited to inflammatory diseases such as crohn's disease, ulcerative colitis, asthma, graft-versus-host disease, allograft rejection, chronic obstructive pulmonary disease, in view of their activity as selective inhibitors of TLR7, TLR8 or TLR 9; autoimmune diseases, such as Graves' disease, rheumatoid arthritis, systemic lupus erythematosus, lupus nephritis, cutaneous lupus, psoriasis; autoinflammatory diseases including cold imidacloprid-associated periodic syndrome (CAPS), TNF receptor-associated periodic syndrome (TRAPS), Familial Mediterranean Fever (FMF), adult still's disease, systemic juvenile idiopathic arthritis, gout, gouty arthritis; metabolic disorders including type 2 diabetes, atherosclerosis, myocardial infarction; destructive bone disorders, such as bone resorption diseases, osteoarthritis, osteoporosis, multiple myeloma-related bone disorders; proliferative disorders, such as acute myeloid leukemia, chronic myeloid leukemia; angiogenic disorders, such as angiogenic disorders including solid tumors, ocular neovasculature, and infantile hemangiomas; infectious diseases, such as sepsis, septic shock, and shigellasis; neurodegenerative diseases, such as alzheimer's disease, parkinson's disease, cerebral ischemia caused by traumatic injury, or neurodegenerative diseases; neoplastic and viral diseases such as metastatic melanoma, kaposi's sarcoma, multiple myeloma and HIV infection, and CMV retinitis, AIDS, respectively.
More specifically, the specific conditions or diseases treatable with the compounds of the present application include, but are not limited to, pancreatitis (acute or chronic), asthma, allergy, adult respiratory distress syndrome, chronic obstructive pulmonary disease, glomerulonephritis, rheumatoid arthritis, systemic lupus erythematosus, scleroderma, chronic thyroiditis, graves ' disease, autoimmune gastritis, diabetes, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopic dermatitis, chronic active hepatitis, myasthenia gravis, multiple sclerosis, inflammatory bowel disease, ulcerative colitis, crohn's disease, psoriasis, graft-versus-host disease, inflammatory responses induced by endotoxins, tuberculosis, atherosclerosis, muscular degeneration, cachexia, psoriatic arthritis, reid's syndrome, gout, traumatic arthritis, rheumatoid arthritis, psoriasis, rheumatoid arthritis, psoriasis, rheumatoid arthritis, psoriasis, rheumatoid arthritis, psoriasis, psoriatic arthritis, psoriasis, and other infections, psoriasis, and other infections, psoriasis, and other infections, Rubella arthritis, acute synovitis, pancreatic beta-cell disease; diseases characterized by massive neutrophil infiltration; rheumatoid spondylitis, gouty arthritis and other arthritic conditions, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcomas, bone resorption diseases, allograft rejection, fever and myalgia due to infection, cachexia secondary to infection, keloid formation, scar tissue formation, ulcerative colitis, fever, influenza, osteoporosis, osteoarthritis, acute myeloid leukemia, chronic myeloid leukemia, metastatic melanoma, kaposi's sarcoma, multiple myeloma, sepsis, septic shock and shigellasis; alzheimer's disease, parkinson's disease, cerebral ischemia or neurodegenerative diseases caused by traumatic injury; angiogenic disorders including solid tumors, ocular neovascularisation and infantile hemangiomas; viral diseases including acute hepatitis infections (including hepatitis a, hepatitis b and hepatitis c), HIV infection and CMV retinitis, AIDS, ARC or malignancy and herpes; stroke, myocardial ischemia, ischemia in stroke heart attacks, organ hypoxia, vascular proliferation, cardiac and renal reperfusion injury, thrombosis, cardiac hypertrophy, thrombin-induced platelet aggregation, endotoxemia and/or toxic shock syndrome, prostaglandin endoperoxidase synthase-2 related disorders, and pemphigus vulgaris. Included in this embodiment are methods of treatment wherein the disorder is selected from lupus (including lupus nephritis and Systemic Lupus Erythematosus (SLE)), crohn's disease, ulcerative colitis, allograft rejection, rheumatoid arthritis, psoriasis, ankylosing spondylitis, psoriatic arthritis, and pemphigus vulgaris. Also included are methods of treatment wherein the disorder is selected from ischemia reperfusion injury (including cerebral ischemia reperfusion injury caused by stroke and cardiac ischemia reperfusion injury caused by myocardial infarction). Another treatment is one in which the disorder is multiple myeloma.
In one embodiment, the compounds of formula (I) are useful for the treatment of cancer, including Waldenstrom's Macroglobulinemia (WM), diffuse large B-cell lymphoma (DLBCL), Chronic Lymphocytic Leukemia (CLL), cutaneous diffuse large B-cell lymphoma, and primary CNS lymphoma.
In addition, inhibitors of TLR7, TLR8, or TLR9 of the present application inhibit the expression of inducible pro-inflammatory proteins, such as prostaglandin endoperoxide synthase-2 (PGHS-2) (also known as cyclooxygenase-2 (COX-2)), IL-1, IL-6, IL-18, chemokines. Thus, other TLR 7/8/9-related conditions include edema, analgesia, fever, and pain (e.g., neuromuscular pain, headache, pain due to cancer, dental pain, and arthritic pain). The compounds of the present application may also be useful in the treatment of viral infections in livestock, such as lentiviral infections, including but not limited to equine infectious anemia virus; or retroviral infections, including feline immunodeficiency virus, bovine immunodeficiency virus, and canine immunodeficiency virus.
Accordingly, the present application provides a method of treating such disorders comprising administering to a subject in need thereof a therapeutically effective amount of at least one compound of formula (I) or a salt thereof. "therapeutically effective amount" is intended to include an amount of a compound of the present application which, when administered alone or in combination, is effective to inhibit autoimmune diseases or chronic inflammatory diseases.
Methods of treating TLR7, TLR8, or TLR 9-associated disorders can include administering a compound of formula (I), either alone or in combination with each other and/or other suitable therapeutic agents that can be used to treat such disorders. Thus, "therapeutically effective amount" is also intended to include combined amounts of the claimed compounds effective to inhibit TLR7, TLR8, or TLR9 and/or to treat diseases associated with TLR7, TLR8, or TLR 9.
Examples of such other therapeutic agents include corticosteroids, rolipram, cafetidine, cytokine inhibitory anti-inflammatory drugs (CSAID), interleukin-10, glucocorticoids, salicylates, nitric oxide and other immunosuppressive agents; nuclear translocation inhibitors such as Deoxyspergualin (DSG); nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, celecoxib, and rofecoxib; steroids, such as prednisone or dexamethasone; antiviral agents, such as abacavir; antiproliferative agents, such as methotrexate, leflunomide, FK506 (tacrolimus, Tacrolimus, and the like,
Figure BDA0001979596660001091
) (ii) a Antimalarial drugs such as hydroxychloroquine; cytotoxic drugs such as amphetamine and cyclophosphamide; TNF-alpha inhibitors, e.g. tenidap, anti-TNF antibodies or soluble TNF receptors and rapamycin (sirolimus or
Figure BDA0001979596660001092
) Or a derivative thereof.
The other therapeutic agents described above, when used in combination with the compounds of the present application, can be used, for example, in the amounts indicated in the Physicians' Desk Reference (PDR) or in the amounts determined by those skilled in the art. In the methods of the present application, such additional therapeutic agents may be administered prior to, concurrently with, or after administration of the compound of the present application. The present application also provides pharmaceutical compositions capable of treating TLR7/8/9 receptor associated disorders, including the diseases mediated by IL-1 family receptors described above.
The compositions of the present application may contain other therapeutic agents as described above and may be formulated, for example, by using conventional solid or liquid vehicles or diluents and pharmaceutical additives of a type appropriate to the desired mode of administration (e.g., excipients, binders, preservatives, stabilizers, flavoring agents, etc.) according to techniques such as those known in the art of pharmaceutical formulation.
Accordingly, the present application also includes compositions comprising one or more compounds of formula (I) and a pharmaceutically acceptable carrier.
By "pharmaceutically acceptable carrier" is meant a medium that is generally accepted in the art for the delivery of biologically active agents to animals, particularly mammals. The pharmaceutically acceptable carrier is formulated according to a number of factors within the knowledge of those skilled in the art. These factors include, but are not limited to, the type and nature of the active agent being formulated; a subject to whom a composition containing an active agent is to be administered; the intended route of administration of the composition; and targeted therapeutic indications. Pharmaceutically acceptable carriers include aqueous and non-aqueous liquid media and a variety of solid and semi-solid dosage forms. Such carriers can include a variety of different ingredients and additives in addition to the active agent, such other ingredients being included in the formulation (e.g., stabilizing the active agent, binder, etc.) for a variety of reasons known to those skilled in the art. For a description of suitable Pharmaceutical carriers and the factors involved in selecting them, reference is made to various readily available sources such as Remington's Pharmaceutical Sciences, 17 th edition (1985), the entire contents of which are incorporated herein by reference.
The compound of formula (I) may be administered by any means suitable for the condition to be treated, which may depend on the need for site-specific treatment or the amount of compound of formula (I) to be delivered.
The present application also includes a class of pharmaceutical compositions comprising a compound of formula (I) together with one or more non-toxic pharmaceutically acceptable carriers and/or diluents and/or adjuvants (collectively referred to herein as "carrier" materials) and optionally other active ingredients. The compounds of formula (I) may be administered by any suitable route, preferably in the form of a pharmaceutical composition suitable for the above route and in a dose effective for the desired treatment. For example, the compounds and compositions of the present application may be administered orally, mucosally, or parenterally (including intravascularly, intravenously, intraperitoneally, subcutaneously, intramuscularly, and intrasternally) in dosage unit formulations containing conventional pharmaceutical carriers, adjuvants, and vehicles. For example, the pharmaceutical carrier may comprise a mixture of mannitol or lactose and microcrystalline cellulose. The mixture may contain other components such as lubricants (e.g. magnesium stearate) and disintegrants (e.g. crospovidone). The carrier mixture may be filled into gelatin capsules or compressed into tablets. The pharmaceutical compositions may be administered, for example, in oral dosage forms or by infusion.
For oral administration, the pharmaceutical composition may, for example, be in the form of: tablets, capsules, liquid capsules, suspensions or liquid formulations. The pharmaceutical compositions are preferably prepared in dosage unit form containing the active ingredient in the specified amounts. For example, the pharmaceutical composition may be provided in the form of a tablet or capsule containing the active ingredient in an amount of about 0.1mg to 1000mg, preferably about 0.25mg to 250mg and more preferably about 0.5mg to 100 mg. The daily dosage suitable for a human or other mammal may vary widely depending on the condition of the patient and other factors, but can be determined using conventional methods.
Any pharmaceutical composition contemplated herein can be delivered orally, e.g., via any acceptable and suitable oral formulation. Exemplary oral formulations include, but are not limited to, tablets, troches, lozenges, aqueous and oily suspensions, dispersible powders or granules, emulsions, hard and soft capsules, liquid capsules, syrups and elixirs, for example. Pharmaceutical compositions intended for oral administration may be prepared according to any method known in the art for the preparation of pharmaceutical compositions intended for oral administration. To provide a pharmaceutically palatable preparation, the pharmaceutical compositions of the present application may contain at least one substance selected from: sweetening agents, flavoring agents, coloring agents, demulcents, antioxidants and preservatives.
Tablets may be prepared, for example, by mixing at least one compound of formula (I) with at least one non-toxic pharmaceutically acceptable excipient suitable for the preparation of tablets. Exemplary excipients include, but are not limited to, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, and sodium phosphate; granulating and disintegrating agents, such as microcrystalline cellulose, croscarmellose sodium, corn starch and alginic acid; binding agents, such as starch, gelatin, polyvinylpyrrolidone and acacia; and lubricating agents, such as magnesium stearate, stearic acid, and talc. In addition, the tablets may be uncoated or coated by known techniques to mask the unpleasant taste of the drug or to delay disintegration and absorption of the active ingredient in the gastrointestinal tract and thereby retain the effect of the active ingredient for a longer period of time. Exemplary water-soluble taste masking materials include, but are not limited to, hydroxypropyl methylcellulose and hydroxypropyl cellulose. Exemplary time delay materials include, but are not limited to, ethyl cellulose and cellulose acetate butyrate.
Hard gelatin capsules may be prepared, for example, by mixing at least one compound of formula (I) with at least one inert solid diluent, such as calcium carbonate, calcium phosphate and kaolin.
Soft gelatin capsules may be prepared, for example, by mixing at least one compound of formula (I) with at least one water-soluble carrier, such as polyethylene glycol, and at least one oily medium, such as peanut oil, liquid paraffin, and olive oil.
Aqueous suspensions may be prepared, for example, by mixing at least one compound of formula (I) with at least one excipient suitable for the preparation of aqueous suspensions. Exemplary excipients suitable for the preparation of aqueous suspensions include, but are not limited to, suspending agents, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, alginic acid, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents, for example, natural phospholipids such as lecithin; condensation products of alkylene oxides with fatty acids, such as polyoxyethylene stearate; condensation products of ethylene oxide with long chain aliphatic alcohols, such as heptadecaethylene-oxycetanol; condensation products of ethylene oxide with partial esters derived from fatty acids and hexitols, for example polyoxyethylene sorbitol monooleate; and condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, such as polyethylene sorbitan monooleate. The aqueous suspensions may also contain at least one preservative, such as ethyl and n-propyl parabens; at least one colorant; at least one flavoring agent; and/or at least one sweetener including, but not limited to, sucrose, saccharin, and aspartame, for example.
Oily suspensions may be formulated, for example, by suspending at least one compound of formula (I) in a vegetable oil, for example arachis oil, olive oil, sesame oil and coconut oil, or in a mineral oil, for example liquid paraffin. Oily suspensions may also contain at least one thickening agent, for example beeswax, hard paraffin and cetyl alcohol. To provide a palatable oily suspension, at least one sweetener as described above and/or at least one flavoring agent may be added to the oily suspension. Oily suspensions may further contain at least one preservative including, but not limited to, for example, antioxidants such as butylated hydroxytoluene and alpha-tocopherol.
Dispersible powders and granules can be prepared, for example, by mixing at least one compound of formula (I) with at least one dispersing and/or wetting agent, at least one suspending agent and/or at least one preservative. Suitable dispersing, wetting and suspending agents are as described above. Exemplary preservatives include, but are not limited to, for example, antioxidants such as ascorbic acid. In addition, dispersible powders and granules may also contain at least one excipient, including but not limited to, for example, sweetening, flavoring and coloring agents.
Emulsions of at least one compound of formula (I) may be prepared, for example, as oil-in-water emulsions. The oily phase of the emulsion comprising the compound of formula (I) may be constituted in known manner from known ingredients. The oil phase may be provided by, but is not limited to, for example, the following oils: vegetable oils, such as olive oil and peanut oil; mineral oils, such as liquid paraffin; and mixtures thereof. Although this phase may comprise only emulsifiers, it may comprise mixtures of at least one emulsifier with a fat or an oil or with both a fat and an oil. Suitable emulsifiers include, but are not limited to, for example, natural phospholipids, such as soy lecithin; esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate; and condensation products of partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. Preferably, a lipophilic emulsifier is used together with a hydrophilic emulsifier which acts as a stabilizer. It is also preferred to include both oils and fats. In addition, the emulsifier or emulsifiers form a so-called emulsifying wax with or without stabilizer or stabilizers and this wax together with the oil and fat forms a so-called emulsifying ointment base which forms the oily dispersed phase of the cream. The emulsions may also contain sweetening, flavoring, preservative and/or antioxidant agents. Emulsifiers and emulsion stabilizers suitable for use in the formulations herein include tween 60, silk fibroin 80, cetearyl alcohol, myristyl alcohol, glyceryl monostearate, sodium lauryl sulfate, glyceryl distearate, alone or with waxes or other materials known in the art.
The compounds of formula (I) may also be delivered intravenously, subcutaneously and/or intramuscularly, for example, via any pharmaceutically acceptable and suitable injectable form. Exemplary injectable forms include, but are not limited to, for example, sterile aqueous solutions containing an acceptable vehicle and solvent (e.g., water, ringer's solution, and isotonic sodium chloride solution); sterile oil-in-water microemulsions; and aqueous or oily suspensions.
Formulations for parenteral administration may be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions may be prepared from sterile powders or granules using one or more of the carriers or diluents mentioned for oral administration in formulations or by using other suitable dispersing or wetting agents and suspending agents. The compounds may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, tragacanth gum, and/or various buffers. Other adjuvants and modes of administration are known in the pharmaceutical art. The active ingredient may also be administered by injection in a composition with a suitable carrier (including saline, dextrose or water) or cyclodextrin (i.e., Captisol), co-solubilizer (i.e., propylene glycol) or micellar solubilizer (i.e., tween 80).
The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1, 3-butanediol. Acceptable vehicles and solvents that can be used are water, ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
Sterile oil-in-water microemulsions for injection may be prepared, for example, as follows: 1) dissolving at least one compound of formula (I) in an oil phase (e.g., a mixture of soybean oil and lecithin); 2) combining an oil phase comprising formula (I) with a mixture of water and glycerol; and 3) processing the combination to form a microemulsion.
Sterile aqueous or oily suspensions may be prepared according to methods known in the art. For example, sterile aqueous solutions or suspensions may be prepared with a non-toxic parenterally acceptable diluent or solvent (e.g., 1, 3-butanediol); and sterile oily suspensions may be formulated with a non-toxic acceptable sterile solvent or suspending medium such as sterile fixed oils (e.g. synthetic mono-or diglycerides) and fatty acids (e.g. oleic acid).
Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the pharmaceutical compositions of the present application include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, Self Emulsifying Drug Delivery Systems (SEDDS) such as D-alpha-tocopheryl polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as tweens, polyethoxylated castor oil such as CREMOPHOR surfactant (BASF) or other similar polymeric delivery matrices, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, Sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycols and lanolin. Cyclodextrins, such as alpha-, beta-, and gamma-cyclodextrins, or chemically modified derivatives such as hydroxyalkyl cyclodextrins (including 2-and 3-hydroxypropyl cyclodextrins) or other solubilizing derivatives may also be advantageously used to improve delivery of compounds having the formulae described herein.
The pharmaceutically active compounds of the present application can be processed according to pharmaceutically conventional methods to produce medicaments for administration to patients, including humans and other mammals. The pharmaceutical compositions may be subjected to conventional pharmaceutical operations (e.g., sterilization) and/or may contain conventional adjuvants (e.g., preservatives, stabilizers, wetting agents, emulsifiers, buffers, etc.). Tablets and pills may also be prepared with an enteric coating. Such compositions may also contain adjuvants such as wetting agents, sweetening, flavoring and perfuming agents.
The amount of compound administered and the dosage regimen for treating a condition with a compound and/or composition of the present application will depend upon a variety of factors including the age, weight, sex and medical condition of the subject, the type of disease, the severity of the disease, the route and frequency of administration and the particular compound used. Thus, the dosage regimen may vary widely, but can be routinely determined using standard methods. Daily dosages of from about 0.001mg/kg body weight to 100mg/kg body weight, preferably from about 0.0025mg/kg body weight to about 50mg/kg body weight, and most preferably from about 0.005mg/kg body weight to 10mg/kg body weight may be suitable. The daily dose may be administered from 1 to 4 times per day. Other dosing schedules include one dose per week and one dose every two days.
For therapeutic purposes, the active compounds of the present application are usually combined with one or more adjuvants suitable for the route of administration in question. If administered orally, the compounds may be mixed with lactose, sucrose, starch powder, cellulose alkanoates, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia, sodium alginate, polyvinylpyrrolidone and/or polyvinyl alcohol, and then tableted or encapsulated for convenient administration. Such capsules or tablets may include a controlled release formulation, which may be provided as a dispersion of the active compound in hydroxypropylmethyl cellulose.
The pharmaceutical compositions herein comprise at least one compound of formula (I) and optionally other substances selected from any pharmaceutically acceptable carriers, adjuvants and vehicles. Alternatively, the compositions of the present application comprise a compound of formula (I) as described herein or a prodrug thereof and a pharmaceutically acceptable carrier, adjuvant or vehicle.
The present application also includes articles of manufacture. Articles of manufacture for use herein are intended to include, but are not limited to, kits and packages. The article of manufacture of the present application comprises: (a) a first container; (b) a pharmaceutical composition located within the first container, wherein the composition comprises: a first therapeutic agent comprising a compound of the present application or a pharmaceutically acceptable salt thereof; and (c) package insert indicating that the pharmaceutical composition is useful for the treatment of cardiovascular and/or inflammatory disorders (as defined above). In another embodiment, the package insert indicates that the pharmaceutical composition can be used in combination with a second therapeutic agent (as defined above) to treat a cardiovascular and/or inflammatory disorder. The article of manufacture may further comprise: (d) a second container, wherein components (a) and (b) are located within the second container and component (c) is located within or outside the second container. Within the first and second containers means that each container contains an item within its boundaries.
The first container is a container for holding a pharmaceutical composition. The container may be used for manufacturing, storage, transport and/or individual/bulk sale. The first container is intended to include a bottle, jar, vial, flask, syringe, tube (e.g., in the case of a cream), or any other container used to manufacture, contain, store, or dispense a pharmaceutical product.
The second container is a container for holding the first container and optionally for holding packaging instructions. Examples of secondary containers include, but are not limited to, boxes (e.g., paperboard or plastic), crates, cartons, bags (e.g., paper or plastic bags), pouches, and covers. The package insert may be physically attached to the outside of the first container via tape, glue, staples, or other attachment methods or it may be left in the second container without being attached to the first container in any physical manner. Optionally, the package insert is located on the outside of the second container. When located on the outside of the second container, the package insert is preferably physically attached via tape, glue, staples or other attachment methods. Alternatively, it may be adjacent to or in contact with the outside of the second container without physical attachment.
The package insert is a label, tag, etc. that records information related to the pharmaceutical composition located in the first container. The information recorded will typically be determined by a regulatory body governing the area where the product is sold, such as the U.S. food and drug administration. In one embodiment, the package insert specifically records the indications for which the pharmaceutical composition has been approved. The package insert may be made of any material from which a person can read the information contained therein or thereon. For example, the package insert is a printing material (e.g., paper, plastic, cardboard, foil, backing paper or plastic, etc.) on which the desired information (e.g., printing or coating) has been formed.
Preparation method
The compounds of the present application can be prepared by a variety of methods known to those skilled in the art of organic synthesis. The compounds of the present application can be synthesized using the methods described below and synthetic methods known in the art of synthetic organic chemistry or variations thereof as understood by those skilled in the art. Preferred methods include, but are not limited to, those described below. All references cited in this application are incorporated by reference in their entirety.
The compounds of the present application can be prepared using the reactions and techniques described in this section. The reaction is carried out in a solvent appropriate to the reagents and materials used and to the conversion carried out. In addition, it will be understood in describing the synthetic methods described below that all of the reaction conditions set forth (including the choice of solvent, reaction atmosphere, reaction temperature, experimental duration, and work-up procedures) are selected to be standard conditions for the reaction, as will be readily understood by those skilled in the art. It will be appreciated by those skilled in the art of organic synthesis that the functional groups present on the various parts of the molecule must be compatible with the reagents and reactions proposed. The above limitations on substituents compatible with the reaction conditions will be apparent to those skilled in the art, and alternative methods must then be used. This will sometimes require a judgment to adjust the order of the synthetic steps or to select a particular protocol that is better than another to obtain the desired compound of the present application. It will also be appreciated that another major problem to be considered in the art in planning any synthetic route is the rational choice of protecting groups for protecting reactive functional groups present in the compounds of the present application. Authoritative literature providing the skilled worker with a number of alternatives is Greene and Wuts (Protective Groups In Organic Synthesis, 3 rd edition, Wiley and Sons, 1999).
The compounds of formula (I) may be prepared by methods as exemplified by reference to the following schemes. As shown herein, the final product is a compound having the same structural formula as formula (I). It will be appreciated that any compound of formula (I) may be prepared via the described scheme by appropriate selection of reagents with appropriate substitutions. Solvents, temperatures, pressures and other reaction conditions can be readily selected by one skilled in the art. The starting materials are either commercially available or readily prepared by one skilled in the art. The composition of the compounds is defined herein or elsewhere in the specification.
As shown in scheme 1, compounds of formula (I) can be prepared starting from substituted 5-bromoindoles (2). 2 can be prepared from 3-formylindole via reduction or from 3H-indole via alkylation. The cross-coupling of transition metal pair 2 with borate 3 is catalyzed, followed by olefin reduction and Boc deprotection to give 4, which can then be coupled with pyridylboronic acid and deprotected to give 6. Alkylation of 6 affords compounds of formula I.
Scheme 1
Figure BDA0001979596660001161
Figure BDA0001979596660001171
In an alternative preparation, bromoindole 2b may first be coupled with boronic ester 3 and reduced. The chlorination and bromination are carried out selectively at the 3-position, followed by the dihalogenated compound 7.
Scheme 2
Figure BDA0001979596660001172
Examples
The compounds of formula (I) and intermediates used in the preparation of the compounds of formula (I) can be prepared using the procedures shown in the examples below and related procedures. The methods and conditions used in these examples, and the actual compounds prepared in these examples, are not intended to be limiting, but rather to demonstrate how the compounds of formula (I) may be prepared. The starting materials and reagents for these examples are generally commercially available or reported in the chemical literature or can be prepared by using procedures described in the chemical literature when not prepared by procedures described in this application.
Abbreviations
Ac: acetyl group
AcOH: acetic acid
ACN: acetonitrile
AIBN: 2, 2-azobisisobutyronitrile
anhyd.: without water
aq.: aqueous solution
BH3DMS: borane dimethyl sulfide
Bn: benzyl radical
Bu: butyl radical
Boc: tert-butoxycarbonyl group
CV: volume of column
DBU: 1, 8-diazabicyclo [5.4.0] undec-7-ene
DCE: dichloroethane
DCM: methylene dichloride
DEA: diethylamine
DIPEA: diisopropylethylamine
DMF: dimethyl formamide
DMAP: dimethylaminopyridine compound
DMF-DMA: n, N-dimethyl formamide dimethyl acetal
DMSO, DMSO: dimethyl sulfoxide
Et3N: triethylamine
EtOAc: ethyl acetate
Et: ethyl radical
EtOH: ethanol
Et2O: ether (A)
H or H 2: hydrogen gas
h. hr or hrs: hour(s)
HATU: o- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate
hex: hexane (C)
i: different from each other
IPA: isopropanol (I-propanol)
HOAc: acetic acid
HCl: hydrochloric acid
HPLC: high pressure liquid chromatography
LAH: lithium aluminum hydride
LC: liquid chromatography
LCMS: liquid chromatography-mass spectrometry
M: molarity of the solution
And (mM): millimolar concentration
Me: methyl radical
MeOH: methanol
MHz: megahertz
min: minute (min)
mins: minute (min)
M+1：(M+H)+
MOM-Cl: chloromethyl methyl ether
MS: mass spectrometry
N or N: is just
NBS: n-bromosuccinimide
NIS: n-iodosuccinimide
nm: nano meter
nM: nanomolar concentration
NMP: n-methylpyrrolidine
Pd/C: palladium on carbon
PdCl2(dppf): [1, 1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (II)
Pd2(dba)3: tris (dibenzylideneacetone) dipalladium
Pd(OAc)2: palladium acetate
Pet ether: petroleum ether
Ph: phenyl radical
The Ret time: retention time
sat.: saturation of
TEA: triethylamine
TFA: trifluoroacetic acid
THF: tetrahydrofuran (THF)
TsCl: 4-tosyl chloride
Generation 2 Xphos precatalyst: (chloro (2-dicyclohexylphosphino-2 ', 4', 6 '-triisopropyl-1, 1' -biphenyl) [2- (2 '-amino-1, 1' -biphenyl) ] palladium (II)
Analytical and preparative HPLC conditions:
method QC-ACN-AA-XB: column: waters Acquity UPLC BEH C18, 2.1X 50mm, 1.7 μm particles; mobile phase A: 5: 95 acetonitrile: water +10mM ammonium acetate; mobile phase B: 95: 5 acetonitrile: water +10mM ammonium acetate; temperature: 50 ℃; gradient: 0-100% B over 3 minutes, then held at 100% B for 0.75 minutes; flow rate: 1.0 mL/min; and (3) detection: UV 220 nm.
And (3) QC method:
method QC-ACN-TFA-XB: column: waters Acquity UPLC BEH C18, 2.1X 50mm, 1.7 μm particles; mobile phase A: 5: 95 acetonitrile: water + 0.1% trifluoroacetic acid; mobile phase B: 95: 5 acetonitrile: water + 0.1% trifluoroacetic acid; temperature: 50 ℃; gradient: 0-100% B over 3 minutes, then held at 100% B for 0.75 minutes; flow rate: 1.0 mL/min; and (3) detection: UV 220 nm.
Method A1: l3 Acquity: column: (LCMS) BEH C18, 2.1X 50mm, 1.7 μm particles; mobile phase: (A) water; (B) acetonitrile; buffering agent: 0.05% TFA; gradient range: 2% -98% B (0min to 1min) 98% B (to 1.5min) 98% -2% B (to 1.6 min); gradient time: 1.6 min; flow rate: 0.8 mL/min; analysis time: 2.2 min; and (3) detection: the detector 1: UV 254 nm; the detector 2: MS (ESI)+)。
Method B1: l2 liquidy (4): column: (LCMS) BEH C18, 2.1X 50mm, 1.7 μm particles; mobile phase: (A) water; (B) acetonitrile; buffering agent: 0.05% TFA; gradient range: 2% -98% B (0min to 1min) 98% B (to 1.5min) 98% -2% B (to 1.5 min); gradient time: 1.8 min; flow rate: 0.8 mL/min; analysis time: 2.2 min; and (3) detection: the detector 1: UV 254 nm; the detector 2: MS (ESI)+)。
Method C1 SCP: column: waters Acquity UPLC BEH C18, 2.1X 50mm, 1.7 μm particles; mobile phase A: 5: 95 acetonitrile: water +10mM ammonium acetate; mobile phase B: 95: 5 acetonitrile: water +10mM ammonium acetate; temperature: 50 ℃; gradient: 0-100% B over 3 minutes, followed by 0.75 minutes at 100% B; flow rate: 1.11 mL/min; and (3) detection: UV 220 nm.
Method D1 SCP: column: waters Acquity UPLC BEH C18, 2.1X 50mm, 1.7 μm particles; mobile phase A: 5: 95 acetonitrile: water + 0.1% trifluoroacetic acid; mobile phase B: 95: 5 acetonitrile: water + 0.1% trifluoroacetic acid; temperature: 50 ℃; gradient: 0-100% B over 3 minutes, then held at 100% B for 0.75 minutes; flow rate: 1.11 mL/min; and (3) detection: UV 220 nm.
Method E1 iPAC: column: waters Xbridge C184.6X 50mm 5 μm particles; mobile phase A: 5: 95 acetonitrile: water +10mM ammonium acetate; mobile phase B: 95: 5 acetonitrile: water +10mM ammonium acetate; temperature: 50 ℃; gradient: 0-100% B over 1 minute; flow rate: 4 mL/min; and (3) detection: UV 220 nm.
Method F1 iPAC: column: waters Acquity BEH C182.1X 50mm 1.7 μm particles; mobile phase A: 5: 95 acetonitrile: water + 0.1% trifluoroacetic acid; mobile phase B: 95: 5 acetonitrile: water + 0.1% trifluoroacetic acid; temperature: 50 ℃; gradient: 0-100% B over 2.20 minutes; flow rate: 0.800 mL/min; and (3) detection: UV 220 nm.
(A) The method comprises the following steps column-Ascentis Express C18 (50X 2.1mm 2.7 μm); mobile phase A: 10mM NH in Water4COOH: ACN (98: 02); mobile phase B: 10mM NH in Water4COOH: ACN (02: 98); gradient: 0-100% B over 3 minutes; the flow rate was 1 mL/min.
(B) The method comprises the following steps Waters Acquity BEH C18 (2.1X 50mm)1.7 μm; buffering agent: 5mM ammonium acetate, adjusted to pH 5 with HCOOH; solvent A: ACN (95: 5); solvent B: ACN (5: 95); the method comprises the following steps: % B: 0 min-5%: 1.1 min-95%: 1.7 min-95%; flow rate: 0.8 mL/min.
(C) The method comprises the following steps column-Ascentis Express C18 (50X 2.1mm 2.7 μm); mobile phase A: HCOOH in 0.1% water; mobile phase B: CAN; temperature: 50 ℃; gradient: 0-100% B over 3 minutes; flow rate: 1.0 mL/min.
(D) The method comprises the following steps Kinetex XB-C18 (75X 3mm)2.6 μm; solvent A: 10mM ammonium formate in water acetonitrile (98: 02); mobile phase B: 10mM ammonium formate in water acetonitrile (02: 98); temperature: 50 ℃; gradient: 0-100% B over 3 minutes; flow rate: 1.1 mL/min; and (3) detection: UV 220 nm.
(E) The method comprises the following steps Column: ascentis Express C18 (50X 2.1) mm, 2.7 μm; mobile phase A: 5: 95 acetonitrile: water +10mM NH4OAc; mobile phase B: 95: 5 acetonitrile: water +10mM NH4OAc; temperature: 50 ℃; gradient: 0-100% B over 3 minutes; flow rate: 1.1 mL/min.
(F) The method comprises the following steps Column: ascentis Express C18 (50X 2.1) mm, 2.7 μm; mobile phase A: 5: 95 acetonitrile: water + 0.1% TFA; mobile phase B: 95: 5 acetonitrile: water + 0.1% TFA; temperature: 50 ℃; gradient: 0-100% B over 3 minutes; flow rate: 1.1 mL/min.
(G) The method comprises the following steps Column: waters Acquity UPLC BEH C18 (2.1X 50mm), 1.7 μm; solvent A: 100% water + 0.05% TFA; solvent B: 100% acetonitrile + 0.05% TFA; gradient: 2-98% B over 1 minute, followed by 0.5 minute hold at 98% B; flow rate: 0.8 mL/min; and (3) detection: UV 220 nm.
(H) The method comprises the following steps Column: acentis Express C18 (50X 2.1mm)1.7 μm, Acentis C8 NH4COOH 5min M; mobile phase A: 10mM ammonium formate: ACN (98: 2); mobile phase B: 10mM ammonium formate: ACN (2: 98); flow rate: 1 mL/min.
(I) Column: sunfire C18 (4.6X 150) mm, 3.5 μm; mobile phase A: 5: 95 acetonitrile: water + 0.05% TFA; mobile phase B: 95: 5 acetonitrile: water + 0.05% TFA; temperature: 50 ℃; gradient: 10-100% B after 12 minutes; flow rate: 1 mL/min.
(J) Column: sunfire C18 (4.6X 150) mm, 3.5 μm; mobile phase A: 5: 95 acetonitrile: water + 0.05% TFA; mobile phase B: 95: 5 acetonitrile: water + 0.05% TFA; temperature: 50 ℃; gradient: 10-100% B over 25 minutes; flow rate: 1 mL/min.
(K) The method comprises the following steps Column: acquity UPLC BEH C18, 3.0X 50mm, 1.7 μm particles; mobile phase A: 5: 95 acetonitrile: water +10mM ammonium acetate; mobile phase B: 95: 5 acetonitrile: water +10mM ammonium acetate; the method comprises the following steps: % B: 0 min-20%: 1.1 min-90%: 1.7 min-90%; flow rate: 0.7 mL/min.
(L): column: kinetex XB-C18 (75X 3mm-2.6 μm); mobile phase A: 10mM ammonium formate: ACN (98: 2); mobile phase B: 10mM ammonium formate: ACN (2: 98); the flow rate was 1 mL/min.
(M): column: acquity BEH C18 (3.0X 50mm)1.7 μm; mobile phase A: 0.1% TFA in water; mobile phase B: 0.1% TFA in ACN; % B: 0 min-20%: 1.0 min-90%: 1.6min 90%; flow rate: 0.7 mL/min.
(N) column: XBridge BEH XP C18(50 × 2.1) mm, 2.5 μm; mobile phase A: 5: 95 acetonitrile: water +10mM ammonium acetate; mobile phase B: 95: 5 acetonitrile: water +10mM ammonium acetate; temperature: 50 ℃; gradient: 0-100% B over 3 minutes; flow rate: 1.1 mL/min; and (3) detection: UV 220 nm.
Intermediates
Intermediate T-1: 4- (2-bromo-3-isopropyl-1H-indol-5-yl) piperidine-1-carboxylic acid tert-butyl ester
Figure BDA0001979596660001221
Intermediate T-1A: 5-bromo-3-isopropyl-1H-indole
Figure BDA0001979596660001222
A250 mL round bottom flask was charged with triethylsilane (8.90g, 77mmol), trichloroacetic acid (6.25g, 38.3mmol), and toluene (50 mL). The solution was heated to 70 ℃ and a solution of 5-bromo-1H-indole (5.0g, 25.5mmol) and acetone (2.247mL, 30.6mmol) in toluene (30mL) was then added dropwise via an addition funnel. The resulting brown solution was heated at 70 ℃ for 1.5 h. The solution was cooled to 10 ℃, quenched with 10% sodium bicarbonate and diluted with ether. The organic layer was separated, dried and concentrated in vacuo to give crude compound. The crude compound was purified by silica gel chromatography eluting with 5% ethyl acetate in hexane to give 5-bromo-3-isopropyl-1H-indole (5.5g, 23.10mmol, 95% yield) as an oil. LC retention time 1.42 min. [D] In that respect MS (E-) m/z: 238.2(M + H).
Intermediate T-1B: 4- (3-isopropyl-1H-indol-5-yl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester
Figure BDA0001979596660001231
To a mixture of 5-bromo-3-isopropyl-1H-indole (5.5g, 23.10mmol) and 4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (7.50g, 24.25mmol) in a 250mL round bottom flask was added THF (50mL) followed by an aqueous solution of dipotassium hydrogen phosphate (12.07g, 69.3mmol, 20 mL). The resulting reaction mixture was degassed with nitrogen for 10 minutes, followed by addition of PdCl2(dppf)-CH2Cl2Adduct (0.472g, 0.577 mmol). The mixture was degassed again for 5 min. The resulting reaction mixture was heated at 75 ℃ for 18 hours. The reaction mixture was diluted with ethyl acetate (100mL), poured into another funnel and washed with water (2 × 50mL), brine (50mL), dried over sodium sulfate and concentrated to give the crude product. The crude material was purified using silica gel chromatography eluting with 15% ethyl acetate in hexane. The fractions were collected and concentrated to give tert-butyl 4- (3-isopropyl-1H-indol-5-yl) -5, 6-dihydropyridine-1 (2H) -carboxylate (6.5g, 83% yield) as an oil. LCMS retention time 1.21 min. [ B ]]。MS(E-)m/z：339(M-H)。
Intermediate T-1C: 4- (3-isopropyl-1H-indol-5-yl) piperidine-1-carboxylic acid tert-butyl ester
Figure BDA0001979596660001232
To a solution of tert-butyl 4- (3-isopropyl-1H-indol-5-yl) -5, 6-dihydropyridine-1 (2H) -carboxylate (7.9g, 23.20mmol) in ethyl acetate (150mL) under a nitrogen atmosphere was added palladium on carbon (0.617g, 0.580 mmol). The vessel was pumped/flushed three times with nitrogen and then evacuated. Hydrogen was introduced via balloon and the mixture was stirred at room temperature for 5 hours. The suspension was filtered through celite and the filtrate was concentrated to give crude compound. The crude residue was purified by silica gel chromatography eluting with 15% ethyl acetate in hexane. The combined fractions were collected and concentrated to give tert-butyl 4- (3-isopropyl-1H-indol-5-yl) piperidine-1-carboxylate (6.5g, 82% yield) as a white solid. LCMS retention time 2.48 min. [C] In that respect MS (E-) m/z: 341 (M-H).
Intermediate T-1:
to a solution of tert-butyl 4- (3-isopropyl-1H-indol-5-yl) piperidine-1-carboxylate (6.3g, 18.40mmol) in DCE (60mL) was added NBS (3.27g, 18.40mmol) dissolved in DCE (50mL) dropwise via an addition funnel at 0 ℃ over 10 min. The resulting brown solution was stirred at room temperature for 20 min. The reaction was quenched with sodium sulfite solution (15 mL). The volatiles were removed. The residue was taken up in DCM (50mL) and the aqueous layer was separated. The organic layer was washed with Na2SO4Dried and concentrated to give crude compound. The crude compound was purified by silica gel chromatography eluting with 15% ethyl acetate in petroleum ether, collecting fractions and concentrating to give tert-butyl 4- (2-bromo-3-isopropyl-1H-indol-5-yl) piperidine-1-carboxylate (6.4g, 83% yield) as a white solid. LCMS retention time 2.58 min. [ H ] ]。MS(E-)m/z：367.2(M-H)。1H NMR (500MHz, chloroform-d) δ 7.84(br.s., 1H), 7.49(d, J ═ 0.9Hz, 1H), 7.22(d, J ═ 8.4Hz, 1H), 7.02(dd, J ═ 8.4, 1.5Hz, 1H), 4.27(br.s., 2H), 3.23(quin, J ═ 7.1Hz, 1H), 2.84(br.s., 3H), 1.88(d, J ═ 13.1Hz, 2H), 1.50(s, 9H), 1.43(d, J ═ 7.2Hz, 6H), 1.24(s, 2H).
Alternative preparation of intermediate T-1
Intermediate T-1A:
a5-liter 4-neck round-bottom flask was charged with triethylsilane (489mL, 3061mmol), trichloroacetic acid (250g, 1530mmol), and toluene (500 mL). The solution was heated to 70 ℃. 5-bromo-1H-indole (200g, 1020mmol) dissolved in acetone (150mL, 2040mmol) and toluene (700mL) was then added dropwise over 30 minutes. After the addition was complete, the resulting solution was heated at 90 ℃ for 3 h. Followed by the dropwise addition of 10% NaHCO at 0 ℃ to 10 ℃3The solution (about 2.5 liters) was quenched until the pH was basic. The organic and aqueous layers were separated and the aqueous layer was extracted with MTBE (2X 1000 mL). The combined organic layers were washed with water and brine solution, and then washed with Na2SO4Dried and concentrated in vacuo to give a brown oil. The crude residue was purified by chromatography on 750g silica gel eluting with PE: EtOAc (9: 1)The remainder. The product was eluted with 8% EtOAc in petroleum ether, collected and concentrated in vacuo at 50 ℃. A light brown viscous liquid was obtained and hexane (100mL) was added. The mixture was stirred and cooled to-40 ℃ to-50 ℃. After 10min, a solid formed, which was filtered and washed with a minimum amount of cold hexane. The compound was dried in vacuo to give 5-bromo-3-isopropyl-1H-indole (215g, 890mmol, 87% yield) as an off-white solid. LCMS MH +: 237.5. HPLC retention time 3.75 min. Method D.
Intermediate T-1B:
in a 2L round bottom flask 5-bromo-3-isopropyl-1H-indole (90g, 378mmol) and tert-butyl 4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -5, 6-dihydropyridine-1 (2H) -carboxylate (140g, 454mmol) were dissolved in THF (1200 mL). Potassium phosphate (241g, 1134mmol) was dissolved in water (300 mL). An aqueous solution was added to the reaction mixture. With N2The reaction mixture was washed. Subsequently adding PdCl to the reaction mixture2(dppf)-CH2Cl2Adduct (7.72g, 9.45 mmol). Again using N2The reaction mixture was washed. The reaction mixture was stirred at 80 ℃ for 18 h. The reaction mixture was filtered through celite and extracted with EtOAc. The combined organic layers were washed with brine, dried (sodium sulfate) and concentrated to remove the solvent. The crude material was purified by silica gel chromatography. The product was collected by elution with 30% EtOAc: PE to give 4- (3-isopropyl-1H-indol-5-yl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (125g, 367 mmol). LCMS MH+: 341.2. HPLC retention time 2.90 min. The method comprises the following steps: column: zorbax SB-18 (50X 4.6mm-5.0 μm); mobile phase A: h210mM NH in O4COOH: ACN (98: 2); mobile phase B: h210mM NH in O 4COOH: ACN (2: 98); flow rate: 1.5/min; gradient: 30% B to 100% B over 4 minutes; UV 220 nm.
Intermediate T-1C:
in a 2L round bottom flask, tert-butyl 4- (3-isopropyl-1H-indol-5-yl) -5, 6-dihydropyridine-1 (2H) -carboxylate (125g, 367mmol) was dissolved in ethyl acetate (1200 mL). Pd/C (15.63g, 14.69mmol) was added and the reaction mixture was stirred under N2And (4) degassing. The reaction mixture was heated at room temperature under N2Stirring for 18 h. About 80% of the starting material was converted to product. The reaction mixture was filtered through celite and concentrated. The crude material was purified by silica gel chromatography. The product was collected by elution with 20% EtOAc: PE to give tert-butyl 4- (3-isopropyl-1H-indol-5-yl) piperidine-1-carboxylate (105g, 307mmol, 84% yield). LCMS MH+: 343.4. HPLC retention time 2.61 min. The method comprises the following steps: column: zorbax SB-18 (50X 4.6mm-5.0 μm); mobile phase A: h210mM NH in O4COOH: ACN (98: 2); mobile phase B: h210mM NH in O4COOH: ACN (2: 98); flow rate: 1.5/min; gradient: 30% B to 100% B over 4 minutes; UV 220 nm.
Intermediate T-1:
in a 2L round bottom flask, tert-butyl 4- (3-isopropyl-1H-indol-5-yl) piperidine-1-carboxylate (100g, 292mmol) was dissolved in 1, 2-dichloroethane (1200 mL). A solution of 1, 2-dichloroethane (400mL) and NBS (52.0g, 292mmol) in THF (800mL) was added dropwise at 0 deg.C. After addition of NBS solution, the reaction mixture was stirred for 30 min. The reaction mass was quenched with 10% sodium thiosulfate solution at 0 ℃ and diluted with DCM. The combined organic layers were washed with brine, dried (sodium sulfate) and concentrated. The crude material was purified by silica gel chromatography. The product was collected by elution with 10% EtOAc: PE. Dibromo products (about 5-10%) were observed. The material was washed with cooled hexane to remove the dibromo product and give 4- (2-bromo-3-isopropyl-1H-indol-5-yl) piperidine-1-carboxylic acid tert-butyl ester (87g, 206mmol, 70.7% yield). LCMS MH +-56: 365.0. HPLC retention time 4.21 min. The method comprises the following steps: column: kinetex XB-C18 (75X 3mm-2.6 μm); mobile phase A: h210mM NH in O4COOH: ACN (98: 02); mobile phase B: h210mM NH in O4COOH: ACN (02: 98); flow rate: 1.0/min; gradient: 20% B to 100% B over 4 minutes; UV 220 nm.
Intermediate T-2: 4- (3-isopropyl-2- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-indol-5-yl) piperidine-1-carboxylic acid tert-butyl ester
Figure BDA0001979596660001261
To a mixture of tert-butyl 4- (2-bromo-3-isopropyl-1H-indol-5-yl) piperidine-1-carboxylate (1.0g, 2.373mmol), 2-dicyclohexylphosphino-2 ', 6' -dimethoxybiphenyl (0.117g, 0.285mmol) and bis (benzonitrile) palladium (II) chloride (0.027g, 0.071mmol) in a 50mL reaction tube was added dioxane (10 mL). The resulting reaction mixture was degassed for 10min and then pinacol diboron (0.456g, 3.56mmol) was added, followed by the dropwise addition of TEA (0.992mL, 7.12 mmol). The solution was degassed again for 5 min. The resulting reaction mixture was heated at 85 ℃ for 3 h. The reaction mixture was concentrated and the crude residue was dissolved in ethyl acetate (100mL), poured into a separatory funnel and washed thoroughly with water (2 × 250 mL). The organic layer was washed with Na2SO4Dried and filtered. The filtrate was concentrated in vacuo to give the crude product. The residue was taken up in DCM (3 mL). The crude material was purified by combiflash system eluting with 12% EtOAc/petroleum ether. After concentration of the various fractions, the product was isolated as a white viscous product (0.75g, 67.5% yield). LCMS retention time 4.27 min. [ H ] ]。MS(E-)m/z：467.3(M-H)。1H NMR (400MHz, chloroform-d) Δ 8.35-8.12(m, 1H), 7.66-7.59(m, 1H), 7.11-7.04(m, 1H), 4.40-4.23(m, 2H), 3.80-3.63(m, 1H), 2.99-2.67(m, 3H), 1.98-1.84(m, 2H), 1.79-1.64(m, 2H), 1.54-1.51(m, 9H), 1.49-1.45(m, 6H), 1.39-1.35(m, 12H).
Alternative preparation of intermediate T-2:
tert-butyl 4- (2-bromo-3-isopropyl-1H-indol-5-yl) piperidine-1-carboxylate (85g, 202mmol) was dissolved in dioxane (850mL) in a 1L round bottom flask. Then 2-dicyclohexylphosphino-2 ', 6' -dimethoxybiphenyl (9.11g, 22.19mmol) and bis (benzonitrile) palladium chloride (3.87g, 10.09mmol) were added. Pinacol diboron (387g, 3026mmol) was added followed by TEA (84mL, 605 mmol). The reaction mixture was flushed with nitrogen for 15-20 min. The reaction mixture was stirred at 90 ℃ for 20 h. The reaction mixture was filtered through celite and quenched with brine solution. Boiling was observed. The reaction mixture was extracted with EtOAc, dried (sodium sulfate) and concentrated. The crude material was purified by silica gel chromatography. The product was collected by elution with 10% EtOAc: PE to give 4- (3-isopropyl-2- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane)Alk-2-yl) -1H-indol-5-yl) piperidine-1-carboxylic acid tert-butyl ester (62.5g, 133mmol, 66.1% yield). LCMS MH +: 469.4. HPLC retention time 3.04 min. The method comprises the following steps: column: zorbax SB-18 (50X 4.6mm-5.0 μm); mobile phase A: h210mM NH in O4COOH: ACN (98: 2); mobile phase B: h210mM NH in O4COOH: ACN (2: 98); flow rate: 1.5/min; gradient: 30% B to 100% B over 4 minutes; UV 220 nm.
Intermediate T-3: 4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidine-1-carboxylic acid tert-butyl ester
Figure BDA0001979596660001271
In N2To a mixture of tert-butyl 4- (2-bromo-3-isopropyl-1H-indol-5-yl) piperidine-1-carboxylate (60g, 142mmol), bis (benzonitrile) palladium (II) chloride (1.639g, 4.27mmol), 2-dicyclohexylphosphino-2 ', 6' -dimethoxybiphenyl (3.51g, 8.54mmol) and anhydrous dioxane (407mL) was added pinacol diboron (62.0mL, 427mmol) and triethylamine (59.5mL, 427mmol) at room temperature. The mixture was heated at 85 ℃ for 5 min. And (4) raw material consumption. After cooling the reaction mixture to room temperature (using an aqueous ice bath to accelerate cooling), 2mL of 2M K was added3PO4And (3) solution. After bubble generation was reduced, the remaining 2M potassium phosphate solution (214mL, 427mmol) was added, followed by 6-bromo-7, 8-dimethyl- [1, 2, 4]]Triazolo [1, 5-a]Pyridine (29.9g, 132mmol) and PdGl 2(dppf)-CH2Cl2Adduct (4.07g, 4.98 mmol). The reaction mixture was stirred at 85 ℃ for 2 h. The reaction was complete. After the mixture was cooled to room temperature, the organic layer (suspension) and the aqueous layer were separated. The top organic layer was a suspension. It was concentrated and dissolved in DCM (1.5L) to give a dark DCM solution and an aqueous layer at the top. Water was removed and DCM extract was washed with Na2SO4Dried, filtered through a pad of celite, washed with DCM and concentrated to give 150g of a crude wet mash. The material was purified by Silica gel chromatography using a Silica 40g Gold column. The column was eluted with DCM and ethyl acetate. When using 50% ethyl acetate: when DCM was eluted, the product was collected to give 4- (2- (7, 8-dimethyl- [1, 2, 4 ] as an off-white solid]Triazolo [1, 5-a]Pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidine-1-carboxylic acid tert-butyl ester (56.9g, 117.0mmol, 82% yield). LCMS MH+: 488.5. HPLC retention time 1.13 min. Method G.1H NMR (499MHz, chloroform-d) Δ 8.45-8.41(m, 1H), 8.36-8.33(m, 1H), 7.90-7.84(m, 1H), 7.66-7.63(m, 1H), 7.39-7.34(m, 1H), 7.17-7.12(m, 1H), 4.39-4.26(m, 2H), 3.04-2.94(m, 1H), 2.92-2.75(m, 3H), 2.72-2.65(m, 3H), 2.27-2.21(m, 3H), 2.00-1.90(m, 2H), 1.83-1.71(m, 2H), 1.54-1.51(m, 9H), 1.42-1.38(m, 6H).
Intermediate T-4: 4- (3-isopropyl-2- (8-methoxy- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidine-1-carboxylic acid tert-butyl ester
Figure BDA0001979596660001281
In N2To a mixture of tert-butyl 4- (2-bromo-3-isopropyl-1H-indol-5-yl) piperidine-1-carboxylate (40g, 95mmol), bis (benzonitrile) palladium (II) chloride (1.092g, 2.85mmol), 2-dicyclohexylphosphino-2 ', 6' -dimethoxybiphenyl (2.338g, 5.70mmol) and anhydrous dioxane (271mL) was added pinacol diboron (41.3mL, 285mmol) and triethylamine (39.7mL, 285mmol) at room temperature. The mixture was heated at 85 ℃ for 10 min. And (4) raw material consumption. After the reaction mixture was cooled to room temperature, 2-5mL of 2M K was added3PO4An aqueous solution. After bubbling was slowed, the remaining 2M potassium phosphate solution (142mL, 285mmol) was added followed by 6-bromo-8-methoxy- [1, 2, 4%]Triazolo [1, 5-a]Pyridine (20g, 88mmol) and PdCl2(dppf)-CH2Cl2Adduct (3.10g, 3.80 mmol). The mixture was heated at 70 ℃ for 1.5 h. After completion of the reaction, the concentrated 81g of crude product was purified by silica gel chromatography (3kg Gold column) eluting with DCM and ethyl acetate. With 35% ethyl acetate: collecting the product with DCM to obtain 4- (3-isopropyl-2- (8-methoxy- [1, 2, 4)]Triazolo [1, 5-a]Pyridin-6-yl) -1H-indol-5-yl) piperidine-1-carboxylic acid tert-butyl ester (52.6g, 107mmol, 11 3% yield). LCMS MH+: 490.1. HPLC retention time 1.08 min. Method G.
Intermediate F-1: 6-bromo- [1, 2, 4] triazolo [1, 5-a ] pyridines
Figure BDA0001979596660001282
Commercial reagents: CAS number 356560-80-0
Intermediate F-2: 6-bromo-8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine
Figure BDA0001979596660001283
To a stirred solution of 5-bromo-3-methylpyridin-2-amine (1.75g, 9.36mmol) in N, N-dimethylformamide (13.04mL, 168mmol) was added DMF-DMA (12.53mL, 94 mmol). The reaction mixture was heated to 130 ℃ overnight. After cooling to room temperature, the volatiles were removed under reduced pressure to give a brown oil. To an ice-cooled stirred solution of the crude product in methanol (100mL) and pyridine (15mL) was added hydroxylamine-O-sulfonic acid (1.587g, 14.03 mmol). The reaction mixture was warmed to room temperature and stirred overnight. The volatiles were removed under reduced pressure and the residue was partitioned between aqueous sodium bicarbonate and ethyl acetate. The aqueous layer was further extracted with ethyl acetate and the combined organic layers were washed sequentially with water (10mL) and saturated brine solution (10mL), dried over magnesium sulfate and concentrated in vacuo to give 6-bromo-8-methyl- [1, 2, 4]Triazolo [1, 5-a]Pyridine (1.98 g). LC-MS: m +1 is 212/214. Rt is 0.80 min. [ A1]。1H NMR(400MHz，DMSO-d6)δ9.20(s，1H)，8.48(s，1H)，7.67(s，1H)，2.55(s，3H)。
Intermediate F-3: 6-bromo-7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine
Figure BDA0001979596660001291
To a 40mL vial with pressure relief septum was added 5-bromo-4-methylpyridin-2-amine (5.00g, 26.7mmol), DMF (10mL), and N, N-dimethylformamide dimethyl acetal (11.99mL, 90 mmol). The vial was heated to 130 ℃ and held for 6 hours. The vial was cooled to room temperature and the volatiles were removed in vacuo. The resulting oil was dissolved in MeOH (5mL) and pyridine (3.24mL, 40.1mmol) and cooled to 0 deg.C. hydroxylamine-O-sulfonic acid (4.53g, 40.1mmol) was added over 15 min and the mixture was warmed to room temperature overnight. The solution was concentrated in vacuo. The resulting white solid was partitioned between EtOAc and saturated sodium bicarbonate. The organic layer was separated and the bicarbonate layer was extracted with EtOAc (2X 50 mL). The combined organics were washed with water (50mL) and brine (50mL), dried over magnesium sulfate, filtered, and concentrated to give 6-bromo-7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine as a white solid. (4.5g, 21.22mmol, 79% yield). LC-MS: m +1 is 212/214. Rt is 0.70 min. [A1] In that respect
Intermediate F-4: 6-bromo-7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridine
Figure BDA0001979596660001292
To a 40mL vial with pressure relief septum was added 5-bromo-3, 4-dimethylpyridin-2-amine (5.00g, 24.87mmol), DMF (10mL), and N, N-dimethylformamide dimethyl acetal (11.15mL, 83 mmol). The vial was heated to 80 ℃ and held for 6 hours. The vial was cooled to room temperature. The volatiles were removed in vacuo and the resulting oil was dissolved in MeOH (5mL) and pyridine (3.02mL, 37.3mmol) and cooled to 0 deg.C. hydroxylamine-O-sulfonic acid (4.22g, 37.3mmol) was added over 15 min and the mixture was warmed to room temperature overnight. The solution was concentrated in vacuo. The resulting white solid was partitioned between EtOAc and 1.5M potassium phosphate solution. The organic layer was separated and the aqueous layer was extracted with EtOAc (2X 50 mL). The combined organics were washed with water (50mL) and brine (50mL), dried over magnesium sulfate, filtered and concentrated to give a white solid. The solid was dissolved in DCM and MeOH and loaded onto 80g silica gel column, which was eluted with 0-100% ethyl acetate in hexane. Concentrating the multiple fractions, and collecting white solid 6-bromo-7, 8-dimethyl- [1, 2, 4] ]Triazolo [1, 5-a]Pyridine (5.2g, 23.00mmol, 92% yield). LC-MS: m +1 is 226/228. Rt is 0.75 min. [ A1]。1H NMR (400MHz, chloroform-d) delta 8.68(s, 1H), 8.26(s, 1H), 2.68(s, 3H), 2.50(s, 3H).
Alternative preparation of intermediate F-4:
to a suspension of 5-bromo-3, 4-dimethylpyridin-2-amine (10g, 49.7mmol) in DMF (50mL) was added 1, 1-dimethoxy-N, N-dimethylmethylamine (15.32mL, 114 mmol). The mixture was heated at 110 ℃ under N2Stirring for 12 h. All starting amines were converted after 12h to intermediate imines (M +1, 256). The reaction mixture was concentrated under high vacuum rotary evaporation to remove volatiles. The solvent DMF remained in the black reaction mixture. The resulting residue was diluted with MeOH (50mL) and pyridine (6.03mL, 74.6 mmol). The mixture was cooled to 0 ℃ and hydroxylamine-O-sulfonic acid (8.88g, 74.6mmol) was added over 15 min. The mixture was stirred at room temperature for 24 h. The reaction was complete and the desired product was found after 19 h. The crude reaction mixture was concentrated to remove volatiles. The resulting yellow solid was dissolved in 200mL EtOAc and washed with saturated NaHCO3The solution (200mL) was slowly quenched and gas was generated during the addition of sodium bicarbonate. The organic layer was separated and the aqueous layer was back-extracted with EtOAc. Combined organic layers with H 2O (30mL), brine (2X 30mL) and Na2SO4And (5) drying. The crude product was purified by silica gel chromatography eluting with EtOAc and hexanes to give 6-bromo-7, 8-dimethyl- [1, 2, 4]]Triazolo [1, 5-a]Pyridine (8g, 35.4mmol, 71.1% yield). LCMS MH+: 226.08. HPLC retention time 0.71 min. Method G.1H NMR (400MHz, chloroform-d) delta 8.79-8.63(m, 1H), 8.39-8.10(m, 1H), 2.81-2.61(m, 3H), 2.57-2.48(m, 3H).
Intermediate F-5: 6-bromo-8-methoxy- [1, 2, 4] triazolo [1, 5-a ] pyridine
Figure BDA0001979596660001301
To a stirred solution of 5-bromo-3-methoxypyridin-2-amine (7.5g, 36.9mmol) in DMF (15mL) was added DMF-DMA (15mL, 112 mmol). The reaction mixture was heated to 130 ℃ overnight. After cooling to room temperature, the volatiles were removed under reduced pressure to give a brown oil. To the direction ofTo an ice-cooled stirred solution of a brown oil in methanol (150mL) and pyridine (20mL) was added hydroxylamine-O-sulfonic acid (6.27g, 55.4 mmol). The reaction mixture was warmed to room temperature and stirred overnight. The volatiles were removed under reduced pressure and the residue was partitioned between aqueous sodium bicarbonate and ethyl acetate. The aqueous layer was further extracted with ethyl acetate and the combined organic layers were washed sequentially with water (10mL) and saturated brine solution (10mL), dried over sodium sulfate and concentrated in vacuo to give the crude product. The residue was taken up in DCM (3 mL). Via combiflash 3% MeOH: 97% CHCl 3And purifying the crude product. Concentrating the multiple fractions, and collecting yellow solid 6-bromo-8-methoxy- [1, 2, 4%]Triazolo [1, 5-a]Pyridine (5.0g, 21.93mmol, 59.4% yield). LCMS: m+1228.5. Rt 1.06min, column: ZORBAX SB C18 (50X 4.6mm, 5.0. mu.M), method: 10mM NH in Water4COOH+ACN。1H NMR(400MHz，DMSO-d6)δ＝4.01(s，3H)，7.26(s，1H)，8.45(s，1H)，8.95(s，1H)。
Intermediate F-6: 6-bromo-8- (methoxymethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridine
Figure BDA0001979596660001311
To a 40mL reaction vial was added 6-bromo-8-methyl- [1, 2, 4%]Triazolo [1, 5-a]Pyridine (2.000g, 9.43mmol), AIBN (0.155g, 0.943mmol), NBS (1.679g, 9.43mmol) and CCl4(15 mL). The vial was sealed and heated to 75 ℃ overnight. The reaction mixture was cooled to room temperature and concentrated to dryness. The residue was used in the next step without purification.
To a 40mL vial was added the above residue, THF (15mL), MeOH (10mL), and aqueous NaOH (28.3mL, 28.3 mmol). The reaction vial was capped and heated to 75 ℃ and held for 1 hour. LC-MS showed complete conversion to product. Water and ethyl acetate were added and the layers were separated. The organics were washed with water and brine, then over Na2SO4Dried, filtered and concentrated to give an off-white solid. LC-MS: m +1 is 242. Rt 1.31 min. [ A1]。1H NMR(400MHz，DMSO-d6)δ9.41-9.28(m，1H)，8.52(s，1H)，7.78-7.65(m，1H)，4.84-4.70(m，2H)，3.42(s，3H)。
Intermediate F-7: 6-2- (2-amino-5-bromo-1, 2-dihydropyridin-3-yl) ethanol
Figure BDA0001979596660001312
To a 100mL 2-necked round-bottomed flask, 2- (2-aminopyridin-3-yl) acetic acid (0.250g, 1.622mmol) and THF (8mL) were added under a nitrogen atmosphere. LAH was added to the solution in portions at 5 ℃. The ice bath was removed and the reaction mixture was heated to reflux overnight. After 16 hours, the solvent had evaporated. Diethyl ether was added. After cooling, the reaction mixture was placed in an ice bath. LAH was quenched with MeOH followed by water. Sodium sulfate was added and the mixture was filtered and washed with diethyl ether. The filtrate was concentrated and then dissolved in DCM (5mL) and cooled to 5 ℃. NBS (0.289g, 1.622mmol) in DCM (2mL) was then added. The reaction mixture was warmed to room temperature. The reaction was quenched with 2mL of 10% sodium sulfite solution. DCM (20mL) and water (20mL) were added and the contents added to a separatory funnel. The layers were separated. The organics were washed with brine, over Na2SO4Dried, filtered and concentrated to give the crude product. LC-MS: m+1＝219。Rt＝0.49min。[A1]. This material was used further in analogy to the general procedure for F-2 to give (6-bromo- [1, 2, 4)]Triazolo [1, 5-a]Pyridin-8-yl) ethanol (0.065g, 73%). LC-MS: m+1＝242/244。Rt＝0.65min。[A1]。
Intermediate F-8: (6-bromo- [1, 2, 4] triazolo [1, 5-a ] pyridin-8-yl) methanol
Figure BDA0001979596660001321
Intermediate F-8 starting from 6-bromo-8-methyl- [1, 2, 4] according to the general procedure for F-6 ]Triazolo [1, 5-a]Pyridine was initially prepared and in the second step no methanol was present. LC-MS: m+1＝228/230。Rt＝0.60min。[A1]。
Intermediate F-9: rac-1- (6-bromo- [1, 2, 4] triazolo [1, 5-a ] pyridin-8-yl) ethan-1-ol
Figure BDA0001979596660001322
To a 40mL reaction vial was added 2-amino-5-bromopyridine-3-carbaldehyde (0.750g, 3.73mmol) and THF (10mL) under nitrogen. The mixture was cooled to-20 ℃ and Et was added via syringe over 20 min23M methyl magnesium chloride in O (4.97mL, 14.92 mmol). The reaction mixture was warmed to room temperature and stirred for 3 hours. The reaction mixture was cooled to-20 ℃ and slowly quenched with saturated ammonium chloride. Water and ethyl acetate were added and the layers were separated. The collected organics were washed with saturated NaCl and Na2SO4Drying, filtering and concentrating to dryness to obtain rac-1- (2-amino-5-bromopyridin-3-yl) ethanol. This material was used further in analogy to the general procedure for F-1 to give rac-1- (6-bromo- [1, 2, 4)]Triazolo [1, 5-a]Pyridin-8-yl) ethan-1-ol (0.53g, 58%). LC-MS: m+1＝242/244。Rt＝0.58min。[A1]。
Intermediate F-10: 2- (6-bromo- [1, 2, 4] triazolo [1, 5-a ] pyridin-8-yl) propan-2-ol
Figure BDA0001979596660001323
To a 40mL reaction vial was added methyl 2-amino-5-bromopyridine-3-carboxylate (1.240g, 5.37mmol) and THF (10.73mL) under a nitrogen atmosphere. The mixture was cooled to-20 ℃ and Et was added via syringe over 20 min 23M methyl magnesium chloride in O (7.16mL, 21.47 mmol). The reaction mixture was warmed to room temperature and stirred for 3 hours. The reaction mixture was cooled to-20 ℃ and the reaction was slowly quenched by addition of saturated ammonium chloride. Water and ethyl acetate were added and the layers were separated. The collected organics were washed with saturated NaCl and Na2SO4Drying, filtering and concentrating to dryness to obtain 2- (2-amino-5-bromopyridin-3-yl) propan-2-ol. LC-MS: m+1＝231.3/233.0。Rt＝0.49min。[A1]. The material continued to be used similarly to the general procedure for F-1To obtain 2- (6-bromo- [1, 2, 4)]Triazolo [1, 5-a]Pyridin-8-yl) propan-2-ol (0.65g, 59%). LC-MS: m+1＝255.6/257.8。Rt＝0.85min。[D1]。
Intermediate F-11: (6-bromo-7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-8-yl) methanol
Figure BDA0001979596660001331
Intermediate F-11A: (2-amino-4-methylpyridin-3-yl) methanol
Figure BDA0001979596660001332
To a 100mL Schlenk flask (dried with a heat gun) was added N- (4-methylpyridin-2-yl) pivaloamide (0.300g, 1.560 mmol). Diethyl ether (5.20mL) was added and the reaction mixture was cooled to-78 ℃. 1.7M t-butyllithium in pentane (2.019mL, 3.43mmol) was then added dropwise via syringe. The reaction mixture was stirred at-78 ℃ for 3 h and then chloromethyl methyl ether (0.142mL, 1.872mmol) was added. The reaction mixture was warmed to room temperature and stirred overnight. The reaction was quenched with water. Ethyl acetate was added to the mixture. The mixture was poured into a separatory funnel and the layers were separated. The organics were washed with water and brine, then over Na 2SO4Dried, filtered and concentrated. The crude oil was purified on silica gel using 0-50% ethyl acetate/hexanes. After concentrating the fractions, N- (3- (methoxymethyl) -4-methylpyridin-2-yl) pivaloamide was collected as a brown oil. The mass was suspended in 4M aqueous HCl and heated to 110 ℃ and held for 48 hours. The reaction mixture was cooled to room temperature, diluted with ether and the contents poured into a separatory funnel. The layers were separated and the organic layer was discarded. The aqueous layer was basified with 1.5M dipotassium hydrogen phosphate solution and the suspension was extracted with ethyl acetate (three times). The combined organics were washed with brine, over Na2SO4Dried, filtered and concentrated to give (2-amino-4-methylpyridin-3-yl) methanol (0.1g, 46%). LC-MS: not observed on the instrument (M)+1). Rt 0.39min (general purpose)UV-through). [ A1]。
Intermediate F-11B: (2-amino-5-bromo-4-methylpyridin-3-yl) methanol
Figure BDA0001979596660001333
To a 40mL reaction vial was added (2-amino-4-methylpyridin-3-yl) methanol (0.200g, 1.448mmol), DCM and NBS (0.258g, 1.448mmol) as a suspension in 5mL DCM. The reaction mixture was stirred for 15 minutes. The reaction was quenched with 10% sodium sulfite solution (1 mL). The reaction mixture was diluted with water and DCM and transferred to a separatory funnel. The layers were separated and the organics were washed with brine, over Na 2SO4Dried, filtered and concentrated to give (2-amino-5-bromo-4-methylpyridin-3-yl) methanol (0.08g, 26%). LC-MS: m+1＝217/219。Rt＝0.45min。[A1]。
Intermediate F-11:
intermediate F-11 was prepared from intermediate F-11B according to the general procedure for F-2 to give (6-bromo-7-methyl- [1, 2, 4)]Triazolo [1, 5-a]Pyridin-8-yl) methanol. LC-MS: m+1＝242/244。Rt＝0.60min。[A1]。
Intermediate F-12: 6-bromo-8- (methoxymethyl) -7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine
Figure BDA0001979596660001341
Intermediate F-12A: 6-bromo-8- (methoxymethyl) -7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine
Figure BDA0001979596660001342
To a 40mL reaction vial were added N- (3- (methoxymethyl) -4-methylpyridin-2-yl) pivaloamide (0.100g, 0.423mmol) and 6N aqueous HCl (2.116mL, 2.116 mmol). The vial was capped and heated to 80 ℃ overnight. The mixture was basified with 1.5M dipotassium hydrogen phosphate solution. With acetic acidThe aqueous layer was extracted with ethyl ester (2X 50 mL). The combined organics were washed with saturated NaCl solution and Na2SO4Drying, filtering and concentrating to give 3- (methoxymethyl) -4-methylpyridin-2-amine (Rt ═ 0.44min, [ a1]). This material was suspended in DCM (4 mL). NBS (0.075g, 0.423mmol) was dissolved in 1mL DCM and added dropwise to the reaction mixture via pipette over 5 min. The reaction was quenched by the addition of 1mL of 10% sodium sulfite solution. The organic layer was removed and concentrated. The residue was purified on silica gel with 0-10% MeOH/DCM. After concentration of the multiple fractions, 5-bromo-3- (methoxymethyl) -4-methylpyridin-2-amine was collected as a brown oil. LC-MS: m +1＝231/233。Rt＝0.53min0.60min。[D1]。
Intermediate F-12:
intermediate F-12 was prepared from intermediate F-12A according to the general procedure for F-1 to give 6-bromo-8- (methoxymethyl) -7-methyl- [1, 2, 4]Triazolo [1, 5-a]Pyridine (0.03g, 30%). LC-MS: m+1＝256/258。Rt＝1.07min0.60min。[A1]。
Intermediate F-13: 2- (6-bromo- [1, 2, 4] triazolo [1, 5-a ] pyridin-8-yl) acetonitrile
Figure BDA0001979596660001343
To a 40mL reaction vial was added (6-bromo- [1, 2, 4)]Triazolo [1, 5-a]Pyridin-8-yl) methanol (0.500g, 2.193mmol) followed by the slow addition of SOCl2(1.600mL, 21.93 mmol). The reaction mixture was stirred at 50 ℃ overnight. The reaction mixture was concentrated and placed under vacuum to remove excess thionyl chloride. Then acetonitrile, water and KCN in water (1mL) (0.714g, 10.96mmol) were added. The reaction vessel was sealed and heated to 50 ℃ overnight. The reaction mixture was diluted with 1.5M dipotassium hydrogen phosphate solution and ethyl acetate was added. The reaction mixture was poured into a separatory funnel and the layers were separated. The organics were washed with brine, then Na2SO4Drying, filtering and concentrating to obtain 2- (6-bromo- [1, 2, 4) as brown solid]Triazolo [1, 5-a]Pyridin-8-yl) acetonitrile (0.21g, 40%). LC-MS: m+1＝236/238。Rt＝0.60min。[A1]。
Intermediate F-14: 6-bromo-8-fluoro-7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine
Figure BDA0001979596660001351
To a 40mL reaction vial was added 3-fluoro-4-methylpyridin-2-amine (0.250g, 1.982mmol) in DCM (5 mL). A suspension of NBS (0.353g, 1.982mmol) in DCM (2mL) was added thereto. The reaction mixture was stirred for 30 minutes. The reaction was quenched by the addition of 5mL of 10% sodium sulfite solution. DCM and water were added and the reaction mixture was poured into a separatory funnel. The layers were separated. The collected organics were washed with brine, over Na 2SO4Drying, filtering and concentrating to obtain 5-bromo-3-fluoro-4-methylpyridin-2-amine. This material was used further in analogy to the general procedure for F-2 to give 6-bromo-8-fluoro-7-methyl- [1, 2, 4]Triazolo [1, 5-a]Pyridine (0.45g, 49%). LC-MS: m+1＝230/232。Rt＝0.71min，0.60min。[A1]。
Intermediate F-15: (6-bromo- [1, 2, 4] triazolo [1, 5-a ] pyridin-7-yl) methanol
Figure BDA0001979596660001352
Intermediate F-15A: 6-bromo-7- (bromomethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridine
Figure BDA0001979596660001353
To a 40mL reaction vial was added 6-bromo-7-methyl- [1, 2, 4%]Triazolo [1, 5-a]Pyridine (0.670g, 3.16mmol), carbon tetrachloride (6.32mL), NBS (0.562g, 3.16mmol), and AIBN (0.052g, 0.316 mmol). The reaction vial was capped and heated at 75 ℃ for 5 hours. The reaction mixture was cooled to room temperature, filtered and washed with CCl4The precipitate was washed. The filtrate was concentrated to give 6-bromo-7- (bromomethyl) - [1, 2, 4, as a pale yellow residue]Triazolo [1, 5-a]Pyridine (0.72g, 7)8％)。LC-MS：M+1＝290/292/294。Rt＝0.75min。[A1]。
Intermediate F-15:
to a 40mL vial was added 6-bromo-7- (bromomethyl) - [1, 2, 4%]Triazolo [1, 5-a]Pyridine (1.000g, 3.44mmol), acetone (11mL), sodium iodide (0.515g, 3.44mmol), and potassium acetate (0.675g, 6.87 mmol). The reaction mixture was capped and heated to 55 ℃ and held for 17 hours. The volatiles were removed under a stream of nitrogen and to the residue was added THF (10mL), 1mL water and sodium hydroxide (2.58mL, 10.31 mmol). The vial was capped and heated at 65 ℃ for 8 hours. The mixture was treated with 1N HCl to about pH 7. Ethyl acetate was added and the layers were separated. The organics were washed with brine, over Na 2SO4Drying, filtering and concentrating to obtain (6-bromo- [1, 2, 4] as white solid]Triazolo [1, 5-a]Pyridin-7-yl) methanol (0.35g, 44%). LC-MS: m+1＝228/230。Rt＝0.54min。[A1]。
Intermediate F-16: acetic acid 2- ((6-bromo- [1, 2, 4] triazolo [1, 5-a ] pyridin-8-yl) oxy) ethyl ester
Figure BDA0001979596660001361
Intermediate F-16A: acetic acid 2- ((2-amino-5-bromopyridin-3-yl) oxy) ethyl ester
Figure BDA0001979596660001362
To a 40mL reaction vial was added 2-amino-5-bromopyridin-3-ol (0.320g, 1.693mmol) and DMF (5mL) under nitrogen. The mixture was cooled to 5 ℃ and NaH (0.102g, 2.54mmol) was added. The reaction mixture was stirred at 5 ℃ for 1 hour. Pure 2-bromoethyl acetate (0.283mL, 2.54mmol) was then added via syringe. The reaction mixture was stirred at 5 ℃ and slowly warmed to room temperature overnight. The mixture was cooled to 5 ℃ and carefully diluted with water. Ethyl acetate was added and the mixture was transferred to a separatory funnel. The layers were separated and the organics were washed with brine, dried over sodium sulfate, filtered and concentrated to give2- ((2-amino-5-bromopyridin-3-yl) oxy) ethyl acetate (0.45g, 97%) as a brown oil. LC-MS: m+1＝275/277。Rt＝0.52min。[A1]。
Intermediate F-16:
intermediate F-16A was used further in analogy to the general procedure for F-1 to give acetic acid 2- ((6-bromo- [1, 2, 4) as a brown solid ]Triazolo [1, 5-a]Pyridin-8-yl) oxy) ethyl ester. LC-MS: m+1＝300/302。Rt＝0.69min。[A1]。
Intermediate F-17: 6-bromo-8- (ethoxymethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridine
Figure BDA0001979596660001371
Intermediate F-17A: 6-bromo-8- (bromomethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridine
Figure BDA0001979596660001372
To a 40mL reaction vial was added 6-bromo-8-methyl- [1, 2, 4%]Triazolo [1, 5-a]Pyridine (2.000g, 9.43mmol), AIBN (0.155g, 0.943mmol), NBS (1.679g, 9.43mmol) and CCl4(15 mL). The vial was sealed and heated to 75 ℃ overnight. The reaction mixture was cooled to room temperature, filtered and washed with CCl4The precipitate was washed. The filtrate was concentrated to dryness to give 6-bromo-8- (bromomethyl) - [1, 2, 4] as a pale yellow residue]Triazolo [1, 5-a]Pyridine (1.9g, 69%). LC-MS: m+1＝290/292/294。Rt＝0.73min。[A1]。
Intermediate F-17:
to a 40mL reaction vial was added 6-bromo-8- (bromomethyl) - [1, 2, 4]Triazolo [1, 5-a]Pyridine (0.300g, 1.031mmol), ethanol (3.44mL), sodium iodide (0.015g, 0.103mmol) and potassium acetate (0.051g, 0.516 mmol). The reaction vial was capped and heated to 55 ℃ overnight. The reaction mixture was cooled to room temperature and concentrated to dryness. Water and ethyl acetate were added and the mixture was transferred to a separatory funnel. Separate layers and use the organic substances successively Washed with water and brine, over Na2SO4Drying, filtering and concentrating to obtain 6-bromo-8- (ethoxymethyl) - [1, 2, 4%]Triazolo [1, 5-a]Pyridine (0.2g, 72%). LC-MS: m+1＝256/258。Rt＝0.79min。[A1]。
The following fragments were prepared in a similar manner to the synthetic methods described above.
TABLE 1
Figure BDA0001979596660001373
Figure BDA0001979596660001381
Figure BDA0001979596660001391
Intermediate F-41: 4- (6-bromo- [1, 2, 4] triazolo [1, 5-a ] pyridin-8-yl) morpholine
Figure BDA0001979596660001392
Intermediate F-41A: 5-bromo-3-iodopyridin-2-amines
Figure BDA0001979596660001401
To a stirred solution of 5-bromopyridin-2-amine (4.0g, 23.12mmol), TFA (2.316mL, 30.1mmol) in DMF (100mL) at 0 deg.C was added NIS (6.76g, 30.1mmol) in portions. The reaction mixture was stirred at 50 ℃ for 16 h. The reaction mixture was quenched with ice cold water and sodium thiosulfate solution (3: 1) by addition of saturated NaHCO3The solution was dissolved (pH adjusted to 8) to precipitate the product and stirred at 0 ℃ for 10 min. The resulting solid compound was collected by filtration to give 5-bromo-3-iodopyridin-2-amine (5.1g, 17.06mmol, 73.8% yield) as a brown solid. MS (E)+) m/z: 298.9 (M). Retention time 1.16min。[K]。
Intermediate F-42B: (E) -N' - (5-bromo-3-iodopyridin-2-yl) -N, N-dimethylformamidine
Figure BDA0001979596660001402
A solution of DMF-DMA (11.42mL, 85mmol) and 5-bromo-3-iodopyridin-2-amine (5.1g, 17.06mmol) in DMF (20.0mL) was stirred at 130 ℃ for 16 h. The reaction mixture was cooled to room temperature and the volatiles were evaporated. The mixture was dried under high vacuum to give (E) -N' - (5-bromo-3-iodopyridin-2-yl) -N, N-dimethylformamidine (6.2g, 17.51mmol, 103% yield) as a brown semi-solid. MS (E) +) m/z: 355.8(M + 2H). Retention time 1.51 min. [ K ]]。
Intermediate F-43C: 6-bromo-8-iodo- [1, 2, 4] triazolo [1, 5-a ] pyridines
Figure BDA0001979596660001403
To a stirred solution of (E) -N' - (5-bromo-3-iodopyridin-2-yl) -N, N-dimethylformamidine (6.1g, 17.23mmol) and pyridine (6.97mL, 86mmol) in MeOH (80.0mL) at 0 deg.C was added hydroxylamine-O-sulfonic acid (3.89g, 34.5 mmol). The reaction mixture was stirred at rt for 16 h. The reaction mixture was quenched with ice-cold water and the volatiles were evaporated. The mixture was dried under high vacuum. The residue was dissolved in saturated NaHCO3The solution was extracted with chloroform (2X 200mL) and washed with brine. The organic layer was dried over sodium sulfate and concentrated. The resulting material was purified by silica gel chromatography. Eluting the compound with 65% ethyl acetate and petroleum ether to obtain light yellow solid 6-bromo-8-iodo- [1, 2, 4%]Triazolo [1, 5-a]Pyridine (1.8g, 5.56mmol, 32.2% yield). MS (E)+) m/z: 325.8. retention time 1.577 min. [ L ]]。
Intermediate F-43:
mixing 6-bromo-8-iodo- [1, 2, 4%]Triazolo [1, 5-a]Pyridine (0.300g, 0.926mmol), morpholine (0.403g, 4.63mmol) and Cs2CO3A stirred mixture of (0.905g, 2.78mmol) in DMF (10.0mL) was degassedAnd 5 min. Then Pd is added2(dba)3(0.085g, 0.093mmol) and Xantphos (0.054g, 0.093 mmol). The reaction mixture was stirred in a microwave system at 120 ℃ for 2.5 h. The reaction mixture was diluted with ethyl acetate, filtered and washed with excess ethyl acetate. The combined organic layers were washed with water, brine, dried over sodium sulfate and evaporated to give the crude material. The crude material was purified using 24g of silica gel column, and the compound was eluted with 35% ethyl acetate and petroleum ether to give 4- (6-bromo- [1, 2, 4] as a pale yellow solid ]Triazolo [1, 5-a]Pyridin-8-yl) morpholine (0.180g, 0.636mmol, 68.6% yield). MS (E)+)m/z：285.0。Rt：1.60min。[L]。
The following examples were prepared according to the general procedure described above for intermediate F-43.
TABLE 2
Figure BDA0001979596660001411
Figure BDA0001979596660001421
Intermediate F-52: 6-bromo-8-cyclopropyl- [1, 2, 4] triazolo [1, 5-a ] pyridine
Figure BDA0001979596660001422
Mixing 6-bromo-8-iodo- [1, 2, 4%]Triazolo [1, 5-a]A solution of pyridine (0.400g, 1.235mmol) and cyclopropylboronic acid (0.318g, 3.70mmol) in a mixture of toluene (10.0mL) and water (2.0mL) was degassed for 5 min. Tricyclohexylphosphine (0.069g, 0.247mmol), Pd (OAc) were then added2(0.028g, 0.123mmol) and Na2CO3(1.852mL, 3.70 mmol). The resulting reaction mixture was stirred in a sealed tube at 100 ℃ for 14 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, filtered and washed with excess ethyl acetate. The combined organic layers were washed with water, brine, dried over sodium sulfate and evaporated to give crude compound. Purification using 40g silica gel columnA crude compound. Eluting the compound with 35% ethyl acetate and petroleum ether to obtain light yellow solid 6-bromo-8-cyclopropyl- [1, 2, 4%]Triazolo [1, 5-a]Pyridine (0.240g, 1.008mmol, 82% yield). MS (E +) m/z: 240.0. rt: 1.05 min. [ M ] A]。
Intermediate F-53: 4- (6-bromo-2-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-8-yl) morpholine
Figure BDA0001979596660001423
Intermediate F-53A: (E) -N' - (5-bromo-3-iodopyridin-2-yl) -N, N-dimethylacetamidine
Figure BDA0001979596660001424
A solution of 1, 1-dimethoxy-N, N-dimethylpropan-2-amine (24.63g, 167mmol) and 5-bromo-3-iodopyridin-2-amine (5.0g, 16.73mmol) in DMF (20.0mL) was stirred at 130 ℃ for 16 h. The reaction mixture was cooled to room temperature. The volatiles were evaporated and the material was dried under high vacuum to give (E) -N' - (5-bromo-3-iodopyridin-2-yl) -N, N-dimethylethamidine (5.8g, 15.76mmol, 94% yield) as a brown semi-solid. MS (E)+)m/z：370.0。Rt：0.68min。[M]。
Intermediate F-53B: 6-bromo-8-iodo-2-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridines
Figure BDA0001979596660001431
To a stirred solution of (E) -N' - (5-bromo-3-iodopyridin-2-yl) -N, N-dimethylethamidine (4.5g, 12.23mmol) and pyridine (4.94mL, 61.1mmol) in methanol (80.0mL) was added hydroxylamine-O-sulfonic acid (2.76g, 24.46mmol) at 0 ℃. The reaction mixture was stirred at rt for 16 h. The reaction was quenched with ice-cold water. The volatiles were evaporated and the resulting material was dried under high vacuum. The residue was dissolved in saturated NaHCO3The solution was extracted with chloroform (2X 200mL) and washed with brine. The organic layer was dried over sodium sulfateAnd concentrated to give the crude material. The crude material was purified using a 40g silica gel column. Eluting the compound with 50% ethyl acetate and petroleum ether to obtain light yellow solid 6-bromo-8-iodo-2-methyl- [1, 2, 4% ]Triazolo [1, 5-a]Pyridine (2.2g, 6.51mmol, 53.2% yield). MS (E)+)m/z：337.9(M)。Rt：1.04min。[L]。
Intermediate F-53:
reacting 6-bromo-8-iodo-2-methyl- [1, 2, 4%]Triazolo [1, 5-a]Pyridine (0.300g, 0.888mmol), morpholine (0.232g, 2.66mmol) and Cs2CO3A stirred mixture of (0.723g, 2.219mmol) in DMF (10.0mL) was degassed for 5 min. Then Xantphos (0.051g, 0.089mmol) and Pd were added2(dba)3(0.081g, 0.089 mmol). The reaction mixture was stirred in a microwave system at 120 ℃ for 2.5 h. The reaction mixture was diluted with ethyl acetate, filtered and washed with excess ethyl acetate. The combined organic layers were washed with water, brine, dried over sodium sulfate and evaporated to give the crude material. The crude material was purified using a 24g silica gel column. Eluting the compound with 80% ethyl acetate and petroleum ether to obtain 4- (6-bromo-2-methyl- [1, 2, 4] light yellow solid]Triazolo [1, 5-a]Pyridin-8-yl) morpholine (0.180g, 0.606mmol, 68.2% yield). MS (E)+)m/z：298.8。Rt：1.08min。[K]。
Intermediate F-54: 6-bromo-8-cyclopropyl-2-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine
Figure BDA0001979596660001432
Reacting 6-bromo-8-iodo-2-methyl- [1, 2, 4%]Triazolo [1, 5-a]A solution of pyridine (0.400g, 1.184mmol) and cyclopropylboronic acid (0.305g, 3.55mmol) in a mixture of toluene (10.0mL) and water (2.0mL) was degassed for 5 min. Then tricyclohexylphosphine (0.066g, 0.237mmol), Pd (OAc) 2(0.027g, 0.118mmol) and Na2CO3(1.775mL, 3.55 mmol). The reaction mixture was stirred in a sealed tube at 100 ℃ for 14 h. The reaction mixture was cooled to room temperature. The mixture was diluted with ethyl acetate, filtered and washed with excess ethyl acetate. The combined organic layers were washed with water, brine, anddrying over sodium sulfate and evaporation gave crude compound. The crude compound was purified using a 24g silica gel column. Eluting the compound with 35% ethyl acetate and petroleum ether to obtain light yellow solid 6-bromo-8-cyclopropyl-2-methyl- [1, 2, 4%]Triazolo [1, 5-a]Pyridine (0.220g, 0.873mmol, 73.7% yield). MS (E)+)m/z：254.0。Rt：1.12min。[K]。
Intermediate F-55: 6-bromo-8-cyclopropyl-7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine
Figure BDA0001979596660001441
Intermediate F-55A: 5-bromo-3-iodo-4-methylpyridin-2-amine
Figure BDA0001979596660001442
To a stirred solution of 5-bromo-4-methylpyridin-2-amine (5.0g, 26.7mmol), TFA (2.471mL, 32.1mmol) in DMF (100mL) at 0 deg.C was added NIS (9.02g, 40.1mmol) in portions. The reaction mixture was stirred at 55 ℃ for 2 h. The reaction was quenched with ice-cold water and sodium thiosulfate solution (3: 1). By addition of saturated NaHCO3The solution (pH adjusted to 8) was stirred at 0 ℃ for 10min to precipitate the product. The solid compound was collected by filtration to give 5-bromo-3-iodo-4-methylpyridin-2-amine (8g, 25.6mmol, 96% yield) as a brown solid. MS (E) +)m/z：314.9。Rt：0.92min。[M]。
Intermediate F-55B: (E) -N' - (5-bromo-3-iodo-4-methylpyridin-2-yl) -N, N-dimethylformamidine
Figure BDA0001979596660001443
A solution of DMF-DMA (10.70mL, 80mmol) and 5-bromo-3-iodo-4-methylpyridin-2-amine (2.5g, 7.99mmol) in DMF (15.0mL) was stirred at 130 ℃ for 16 h. The reaction mixture was cooled to room temperature and the volatiles were evaporated. The material was dried under high vacuum to give crude (E) -N' - (5-bromo-3-iodo) as a brown semisolid-4-methylpyridin-2-yl) -N, N-dimethylformamidine (2.8g, 7.61mmol, 95% yield). MS (E)+)m/z：370.1。Rt：1.59min。[K]。
Intermediate F-55C: 6-bromo-8-iodo-7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridines
Figure BDA0001979596660001451
To a stirred solution of (E) -N' - (5-bromo-3-iodo-4-methylpyridin-2-yl) -N, N-dimethylformamidine (2.8g, 7.61mmol) and pyridine (3.08mL, 38.0mmol) in methanol (60.0mL) at 0 deg.C was added hydroxylamine-O-sulfonic acid (1.290g, 11.41 mmol). The reaction mixture was stirred at rt for 16 h. The reaction was quenched with ice-cold water. The volatiles were evaporated and the mixture was dried under high vacuum. The residue was dissolved in saturated NaHCO3Of the solution, it was extracted with chloroform (2X 150mL) and washed with brine. The organic layer was dried over sodium sulfate and concentrated to give the crude product. The crude product was purified by silica gel chromatography. Eluting the compound with 65% ethyl acetate and petroleum ether to obtain light yellow solid 6-bromo-8-iodo-7-methyl- [1, 2, 4% ]Triazolo [1, 5-a]Pyridine (1.5g, 4.44mmol, 58.3% yield). MS (E)+) m/z: 338.2 (M). Retention time 1.11 min. [ K ]]。
Intermediate F-55:
reacting 6-bromo-8-iodo-7-methyl- [1, 2, 4%]Triazolo [1, 5-a]A solution of pyridine (0.400g, 1.184mmol) and cyclopropylboronic acid (0.305g, 3.55mmol) in a mixture of toluene (15.0mL) and water (3.0mL) was degassed for 5 min. Then tricyclohexylphosphine (0.066g, 0.237mmol), Pd (OAc)2(0.027g, 0.118mmol) and Na2CO3(1.775mL, 3.55 mmol). The reaction mixture was stirred in a sealed tube at 100 ℃ for 14 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, filtered and washed with excess ethyl acetate. The combined organic layers were washed with water, brine, dried over sodium sulfate and evaporated to give crude compound. The crude compound was purified by silica gel chromatography. Eluting the compound with 35% ethyl acetate and petroleum ether to obtain light yellow solid 6-bromo-8-cyclopropyl-7-methyl- [1, 2, 4%]Triazolo [1, 5-a]Pyridine (0.280g, 1.111mmol, 94% yield). MS (E)+)m/z：254.0。Rt：2.11min。[L]。
Intermediate F-56: 6-bromo-8-methyl-2- (trifluoromethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridine
Figure BDA0001979596660001452
Intermediate F-56A: 5-bromo-3-methyl-1 lambda4-pyridine-1, 2-diamine 2, 4, 6-trimethylbenzene sulfonate
Figure BDA0001979596660001453
To a stirred solution of ethyl mesitylenesulfonylacetoxyhydroxamate (3.05g, 10.69mmol) in dioxane (20mL) cooled to 0 ℃ was added perchloric acid (1.074g, 10.69 mmol). The mixture was stirred at ambient temperature for 30 min. The reaction mass was quenched with ice-cold water, extracted with dichloromethane (100mL), dried over sodium sulfate and concentrated to give crude 1-amino-5-bromo-3-methyl-1. lambda4-pyridin-2-ammoniumsulfate 2, 4, 6-trimethylbenzenesulfonate. To a stirred solution of 5-bromo-3-methylpyridin-2-amine (2g, 10.69mmol) in DCM (10mL) at 0 deg.C was added 1-amino-5-bromo-3-methyl-1. lambda4-pyridin-2-ammoniumsulfate 2, 4, 6-trimethylbenzenesulfonate. The reaction mixture was stirred at ambient temperature for 1 h. The reaction mixture was diluted with water (25mL), extracted with DCM (2 × 100mL), dried over sodium sulfate and concentrated to give 1, 2-diamino-5-bromo-3-methylpyridin-1-ium 2, 4, 6-trimethylbenzenesulfonate (2.1g, 93%) as a white solid.1H NMR (300MHz, chloroform-d) δ 7.91(br.s., 1H), 7.63(d, J15.9 Hz, 1H), 7.28(s, 2H), 6.89(s, 1H), 3.72(s, 1H), 2.81-2.47(m, 6H), 2.36-2.02(m, 6H), 1.23(t, J7.0 Hz, 2H).
Intermediate F-56:
to a stirred solution of 1, 2-diamino-5-bromo-3-methylpyridin-1-ium 2, 4, 6-trimethylbenzenesulfonate (1g, 2.141mmol) in MeOH (25mL) at 0 deg.C was added trifluoroacetic anhydride (0.351mL, 2.486 mmol). Will be reversed The mixture was stirred at the same temperature for 10 min. Et was then added3N (0.346mL, 2.486mmol) and the reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was concentrated. The reaction was quenched with water (25 mL). The reaction mixture was extracted with EtOAc (2X 100mL), dried over sodium sulfate and concentrated to give 6-bromo-8-methyl-2- (trifluoromethyl) - [1, 2, 4]]Triazolo [1, 5-a]Pyridine. The crude material was purified by silica gel chromatography and eluted with 40% EtOAc in hexanes to give 6-bromo-8-methyl-2- (trifluoromethyl) - [1, 2, 4, an off white solid]Triazolo [1, 5-a]Pyridine (500mg, 71.8%). LC retention time 1.28 min. [ K ]]。MS(E-)m/z：280.0(M+H)。
Intermediate F-57: 6-bromo-8-methoxy-2- (trifluoromethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridine
Figure BDA0001979596660001461
Intermediate F-57A: 3, 5-dibromo-1. lambda4-pyridine-1, 2-diamine 2, 4, 6-trimethylbenzene sulfonate
Figure BDA0001979596660001462
To a stirred solution of ethyl mesitylenesulfonylacetoxyhydroxamate (2.266g, 7.94mmol) in dioxane (20mL) cooled to 0 ℃ was added perchloric acid (1.074g, 10.69 mmol). The reaction mixture was stirred at ambient temperature for 30 min. The reaction was quenched with ice-cold water. The reaction mixture was extracted with dichloromethane (100mL), dried over sodium sulfate and concentrated to give crude 1-amino-3, 5-dibromo-1. lambda 4-pyridin-2-ammoniumsulfate 2, 4, 6-trimethylbenzenesulfonate. To a stirred solution of 3, 5-dibromopyridin-2-amine (2g, 7.94mmol) in DCM (10mL) at 0 deg.C was added 1-amino-3, 5-dibromo-1. lambda4-pyridin-2-ammoniumsulfate 2, 4, 6-trimethylbenzenesulfonate. The reaction mixture was stirred at ambient temperature for 1 h. The reaction mixture was diluted with water (25mL), extracted with DCM (2X 100mL), dried over sodium sulfate and concentrated to give 1, 2-diamino-3, 5-dibromopyridin-1-ium 2, 4, 6-trimethyl as a white solidBenzenesulfonate (2.1g, 93.5%).1H NMR(400MHz，DMSO-d6)δ＝7.88(d，J＝2.0Hz，1H)，7.70(d，J＝2.0Hz，1H)，7.12(s，1H)，6.70(s，4H)，3.56(s，1H)，2.10(s，6H)。
Intermediate F-57B: 6, 8-dibromo-2- (trifluoromethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridine
Figure BDA0001979596660001471
To a stirred solution of 1, 2-diamino-3, 5-dibromopyridin-1-ium 2, 4, 6-trimethylbenzenesulfonate (1g, 2.141mmol) in MeOH (25mL) cooled to 0 deg.C was added trifluoroacetic anhydride (0.351mL, 2.486 mmol). The reaction mixture was stirred for 10 min. Addition of Et3After N (0.346mL, 2.486mmol), the reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was concentrated, quenched with water (25mL), extracted with EtOAc (2X 100mL), dried over sodium sulfate and concentrated to give 6, 8-dibromo-2- (trifluoromethyl) - [1, 2, 4] o]Triazolo [1, 5-a]Pyridine. The crude material was purified by silica gel chromatography eluting with 40% EtOAc in hexanes to give 6, 8-dibromo-2- (trifluoromethyl) - [1, 2, 4] as an off white solid ]Triazolo [1, 5-a]Pyridine (650mg, 73.8%). LC retention time 1.37 min. [ K ]]。MS(E-)m/z：344.0(M+H)。
Intermediate F-57:
to a solution of 6, 8-dibromo-2- (trifluoromethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridine (350mg, 1.015mmol) in acetonitrile (15mL) was added sodium methoxide (54.8mg, 1.015 mmol). The resulting mixture was stirred at 85 ℃ for 1 h. The reaction mixture was quenched with water (20mL), extracted with EtOAc (2X 50mL), dried over sodium sulfate and concentrated to give 6-bromo-8-methoxy-2- (trifluoromethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridine. The crude material was purified by silica gel chromatography and eluted with 50% EtOAc in hexanes to give 6-bromo-8-methoxy-2- (trifluoromethyl) - [1, 2, 4] triazolo [1, 5-a ] pyridine (160mg, 53.5%) as a white solid. LC retention time 1.26 min. [K] In that respect MS (E-) m/z: 294.0 (M-H).
Intermediate F-58: 6-bromo- [1, 2, 4] triazolo [1, 5-a ] pyridin-2-amine
Figure BDA0001979596660001472
Commercial reagents: CAS number 356560-80-0.
Intermediate F-59: 6-chloro-8-trideuteromethyl- [1, 2, 4] triazolo [1, 5-a ] pyridine
Figure BDA0001979596660001481
8-bromo-6-chloro- [1, 2, 4-]Triazolo [1, 5-a]Pyridine was prepared following the general procedure for F-2 starting from 3-bromo-5-chloropyridin-2-amine. LC retention time 0.67 min. [ TS1]。MS(ES+)m/z：233.9(M+H)。
8-bromo-6-chloro- [1, 2, 4- ]Triazolo [1, 5-a]A solution of pyridine (150mg, 0.645mmol) in THF (5.0mL) was degassed with nitrogen for 5 minutes. Iron (III) acetylacetonate (22.79mg, 0.065mmol) was added. The pale yellow solution turned red and was degassed again and then evacuated and backfilled with nitrogen three times. Trideuterated methyl magnesium iodide (0.97mL, 0.97mmol) was added and the reaction mixture was stirred at room temperature for 30 minutes. Upon completion, the reaction mixture was diluted with dichloromethane (20mL), ammonium chloride (10mL) and water (10 mL). The layers were separated and the aqueous layer was extracted with dichloromethane (2X 15 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to give a crude residue which was purified by silica gel chromatography eluting with hexane/ethyl acetate 0-70% to give 6-chloro-8-trideuteromethyl- [1, 2, 4%]Triazolo [1, 5-a]Pyridine (41mg, 0.240mmol, 37.2% yield). LC retention time 0.64 min. [ TS1]。MS(ES+)m/z：171.08(M+H)。1H NMR (400MHz, chloroform-d) δ 8.50(d, J ═ 2.0Hz, 1H), 8.30(s, 1H), 7.29(d, J ═ 2.0Hz, 1H).
Example 1
6- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridine
Figure BDA0001979596660001482
Intermediate 1A: 4- (2- ([1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidine-1-carboxylic acid tert-butyl ester
Figure BDA0001979596660001483
To tert-butyl 4- (3-isopropyl-2- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-indol-5-yl) piperidine-1-carboxylate (50mg, 0.107mmol), 6-bromo- [1, 2, 4 mmol]Triazolo [1, 5-a]To a stirred solution of pyridine (31.7mg, 0.160mmol) in tetrahydrofuran (5mL) and water (0.5mL) was added potassium phosphate (68.0mg, 0.320 mmol). The solution was degassed with nitrogen for 10 min. Then PdCl is added2(dppf) (7.81mg, 10.67. mu. mol) and the solution was degassed again for 10 min. The reaction mixture was heated to 75 ℃ and held for 16 h. Reaction progress was monitored by LCMS. The reaction was filtered through a bed of celite, washed with EtOAc and concentrated to give 4- (2- ([1, 2, 4)]Triazolo [1, 5-a]Pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidine-1-carboxylic acid tert-butyl ester (50mg, 0.109 mmol). The material was used directly in the next step without further purification.
Example 1:
to 4- (2- ([1, 2, 4))]Triazolo [1, 5-a]To a stirred solution of pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidine-1-carboxylic acid tert-butyl ester (50mg, 0.109mmol) in DCM (2mL) was added 1, 4-dioxane (4N HCl) (0.2 mL). The reaction mixture was stirred at rt for 16 h. Reaction progress was monitored by LCMS. The reaction mixture was concentrated and the crude material was purified by preparative LC/MS using the following conditions: waters Xbridge C18, 19X 150mm, 5 μm; protection of the column: waters Xbridge C18, 19X 10mm, 5 μm; mobile phase A: 5: 95 acetonitrile: water + 0.1% TFA; mobile phase B: 95: 5 acetonitrile: water + 0.1% TFA; gradient: 2-20% B over 25 minutes, then 10 minutes at 20% B and 5 minutes at 100% B; flow rate: 15 mL/min. The product-containing fractions were combined and dried using a Genevac centrifugal evaporator. The yield of the product was 5.4mg and its purity assessed by LCMS analysis was 100%. Two kinds of Analytical LC/MS injection was used to determine final purity. Injection 1 conditions: column: ascentis Express C18 (50X 2.1) mm, 2.7 μm; mobile phase A: 5: 95 acetonitrile: water +10mM NH4OAc; mobile phase B: 95: 5 acetonitrile: water +10mM NH4OAc; temperature: 50 ℃; gradient: 0-100% B over 3 minutes; flow rate: 1.1 mL/min. Injection 2 conditions: column: ascentis Express C18 (50X 2.1) mm, 2.7 μm; mobile phase A: 5: 95 acetonitrile: water + 0.1% TFA; mobile phase B: 95: 5 acetonitrile: water + 0.1% TFA; temperature: 50 ℃; gradient: 0-100% B over 3 minutes; flow rate: 1.1 mL/min. LCMS MH+360. The retention time was 0.66 min. [ A1]. Proton NMR was obtained in deuterated DMSO.1H NMR(400MHz，DMSO-d6)δ＝11.24(s，1H)，9.01(d，J＝1.0Hz，1H)，8.66-8.55(m，1H)，8.03-7.96(m，1H)，7.79(dd，J＝9.0，1.5Hz，1H)，7.57(s，1H)，7.35(d，J＝8.5Hz，1H)，7.02(dd，J＝8.3，1.3Hz，1H)，3.41(d，J＝12.0Hz，2H)，3.30-3.23(m，1H)，3.10-3.00(m，2H)，2.96-2.90(m，1H)，2.03-1.94(m，2H)，1.91-1.84(m，2H)，1.45(d，J＝7.0Hz，6H)。
Example 2
6- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) -8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine hydrochloride
Figure BDA0001979596660001491
Intermediate 2A: 4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidine-1-carboxylic acid tert-butyl ester
Figure BDA0001979596660001501
The preparation was carried out in two batches and combined for work-up.
Batch 1: to a mixture of tert-butyl 4- (2-bromo-3-isopropyl-1H-indol-5-yl) piperidine-1-carboxylate (10g, 23.73mmol), bis (benzonitrile) palladium (II) chloride (0.182g, 0.475mmol), 2-dicyclohexylphosphino-2 ', 6' -dimethylphosphino To a mixture of oxybiphenyl (0.390g, 0.949mmol) in dioxane (80mL) was added pinacol diboron (8.61mL, 59.3mmol) and triethylamine (6.62mL, 47.5 mmol). The mixture was heated at 85 ℃ for 5 min. After cooling to room temperature, 2M potassium phosphate solution (35.6mL, 71.2mmol) was slowly added. Then adding 6-bromo-8-methyl- [1, 2, 4 ] in sequence]Triazolo [1, 5-a]Pyridine (4.53g, 21.36mmol) and PdCl2(dppf)-CH2Cl2Adduct (0.775g, 0.949 mmol). The reaction mixture was stirred at 65 ℃ for 30 min.
Batch 2: to a mixture of tert-butyl 4- (2-bromo-3-isopropyl-1H-indol-5-yl) piperidine-1-carboxylate (30g, 71.2mmol), bis (benzonitrile) palladium (II) chloride (0.546g, 1.424mmol) and 2-dicyclohexylphosphino-2 ', 6' -dimethoxybiphenyl (1.169g, 2.85mmol) in dioxane (240mL) was added pinacol diboron (25.8mL, 178mmol) and triethylamine (19.85mL, 142mmol) under nitrogen in a 1L round bottom flask. The mixture was heated at 85 ℃ for 5 min. After cooling to room temperature, the first 10mL of 2M potassium phosphate solution (107mL, 214mmol) was added very slowly first. When there are no more bubbles, add the remaining K quickly3PO4Solution, then adding 6-bromo-8-methyl- [1, 2, 4 ]]Triazolo [1, 5-a]Pyridine (13.59g, 64.1mmol) and PdCl 2(dppf)-CH2Cl2Adduct (2.326g, 2.85 mmol). The reaction mixture was stirred at 65 ℃ for 1 h.
The two batches were combined and used for post-treatment. The aqueous layer was removed and the organic layer was washed with brine, over Na2SO4Dried, filtered through a pad of celite and concentrated to give a dark oil (87 g). The material was purified by silica gel chromatography (hexane/ethyl acetate as eluent) to give 29g of product. LCMS MH+430.1. The retention time was 0.63 min. [ C1]。1H NMR(400MHz，DMSO-d6)δ11.11(s，1H)，8.80(d，J＝0.7Hz，1H)，8.53(s，1H)，7.65-7.52(m，2H)，7.30(d，J＝8.4Hz，1H)，7.02(dd，J＝8.4，1.5Hz，1H)，4.19-4.04(m，2H)，3.28-3.19(m，1H)，2.96-2.70(m，3H)，2.63(s，6H)，2.38-2.26(m，1H)，1.80(d，J＝12.6Hz，2H)，1.56(qd，J＝12.4，4.0Hz，2H)，1.47-1.38(m，12H)。
Alternative preparation of intermediate 2A:
to a 500mL round bottom glass flask was added tert-butyl 4- (2-bromo-3-isopropyl-1H-indol-5-yl) piperidine-1-carboxylate (11g, 26.1mmol), bis (benzonitrile) palladium (II) chloride (0.200g, 0.522mmol), 2-dicyclohexylphosphino-2 ', 6' -dimethoxybiphenyl (0.429g, 1.044mmol), and dioxane (87 mL). Nitrogen was bubbled through the reaction mixture over 5 min. Then pinacol diboron (9.47ml, 65.3mmol) and triethylamine (9.10mi, 65.3mmol) were added to the reaction mixture. The front 1/3 triethylamine was added slowly in small portions and then the remainder 2/3 was added rapidly. The reaction mixture was heated at 85 ℃ under N2Heating for 10 min. The reaction temperature reached 100 ℃. The reaction mixture was cooled to room temperature with an ice water bath. Then 2M potassium phosphate solution (39.2mL, 78mmol) was added. Front 1/10 was added slowly. When there are no more bubbles, add the remaining K 3PO4Solution, then adding 6-bromo-8-methyl- [1, 2, 4 ]]Triazolo [1, 5-a]Pyridine (4.98g, 23.49mmol), PdCl2(dppf)-CH2Cl2The adduct (0.853g, 1.044mmol) was washed with dioxane (10 mL). The mixture was heated at 65 ℃ under N2Heating for 1 h. After the mixture was cooled to room temperature, the organic layer and the aqueous layer were separated. The flask was washed with EtOAc during transfer. The organic layer was washed with brine, over Na2SO4Dried, filtered through a pad of celite and concentrated to give 44.4g of a crude oil. It was purified by silica gel chromatography using 1.5kg silica gel column. The column was eluted with hexane and ethyl acetate. The product was purified with 60% ethyl acetate: hexane elution gave 4- (3-isopropyl-2- (8-methyl- [1, 2, 4 ] methyl) as a light-colored foam]Triazolo [1, 5-a]Pyridin-6-yl) -1H-indol-5-yl) piperidine-1-carboxylic acid tert-butyl ester (9.27g, 19.58mmol, 75% yield). LCMS MH+: 474.3. HPLC retention time 1.15 min. Method G.1H NMR (400MHz, chloroform-d) Δ 8.61-8.54(m, 1H), 8.43-8.38(m, 1H), 7.96-7.88(m, 1H), 7.70-7.64(m, 1H), 7.48-7.44(m, 1H), 7.40-7.35(m, 1H), 7.17-7.09(m, 1H), 4.40-4.23(m, 2H), 3.40-3.26(m, 1H), 2.75(s, 6H), 1.98-1.89(m, 2H), 1.85-1.67(m, 2H), 1.53(m, 12H), 1.52-1.49(s, 3H).
Example 2:
to 4- (3-isopropyl-2- (8-methyl- [1, 2, 4) via syringe]Triazolo [1, 5-a]To a stirred solution of pyridin-6-yl) -1H-indol-5-yl) piperidine-1-carboxylic acid tert-butyl ester (29g, 61.2mmol) in DCM (102mL) was added 4M HCl in dioxane (77mL, 306 mmol). A temperature increase of a few degrees was observed. The solution became a suspension during the addition, then became a clear solution, then became a re-suspension again. MeOH (306mL) was added to give a clear solution. LCMS showed reaction was nearly complete after 2.5h at rt. The reaction mixture was concentrated under reduced pressure with a water bath (T ═ 45 ℃) and subsequently diluted with ether (200 mL). The product was collected by filtration to give 6- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) -8-methyl- [1, 2, 4]Triazolo [1, 5-a]Pyridine dihydrochloride. LC-MS: m +1 is 374. Rt is 0.80 min. [ A1]。1H NMR(400MHz，DMSO-d6)δ11.10(s，1H)，8.80(d，J＝0.7Hz，1H)，8.54(s，1H)，7.66-7.50(m，2H)，7.30(d，J＝8.3Hz，1H)，7.02(dd，J＝8.4，1.5Hz，1H)，4.09(q，J＝5.3Hz，1H)，3.38-3.23(m，6H)，3.18(d，J＝5.3Hz，2H)，3.06(d，J＝11.5Hz，1H)，2.74-2.59(m，4H)，1.75(d，J＝10.0Hz，2H)，1.68-1.52(m，2H)，1.51-1.37(m，6H)。
Alternative preparation of example 2:
to 4- (3-isopropyl-2- (8-methyl- [1, 2, 4 ] methyl) via syringe at room temperature]Triazolo [1, 5-a]To a stirred solution of pyridin-6-yl) -1H-indol-5-yl) piperidine-1-carboxylic acid tert-butyl ester (7.45g, 15.73mmol) in DCM (40mL) was added 4M HCl in dioxane (35.4mL, 142 mmol). The solution became a suspension during the addition, then became a clear solution, then became a re-suspension again. MeOH (100mL) was added to give a clear solution. The reaction was completed within 2 h. The reaction mixture was concentrated under reduced pressure and then diluted with ether (200 mL). The desired product, HCl salt, was collected by filtration to give yellow 6- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) -8-methyl- [1, 2, 4 ]Triazolo [1, 5-a]Pyridine hydrochloride (6.4g, 15.64mmol, 99.4% yield). LCMS MH+: 374.1. HPLC retention time 0.64 min. Method G.
The following examples were prepared according to the general procedures disclosed in examples 1 and 2.
TABLE 3
Figure BDA0001979596660001521
Example 4
6- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) -7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridine dihydrochloride
Figure BDA0001979596660001531
At room temperature to 4- (2- (7, 8-dimethyl- [1, 2, 4)]Triazolo [1, 5-a]To a stirred suspension of pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidine-1-carboxylic acid tert-butyl ester (37.8g, 78mmol) in DCM (97mL) and MeOH (291mL) was added 4M HCl in dioxane (97mL, 388mmol) to give a clear solution. After a few hours, the reaction mixture turned into a white suspension. The reaction was complete after 4 h. The reaction mixture was concentrated under reduced pressure and then diluted with ether (250 mL). The product, the di-HCl salt, was collected by filtration to give 6- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) -7, 8-dimethyl- [1, 2, 4] as an off-white solid]Triazolo [1, 5-a]Pyridine 2HCl (34.66g, 75mmol, 97% yield). LCMS MH+: 388.3. HPLC retention time 1.26 min. Method QC-ACN-AA-XB.1H NMR(500MHz，DMSO-d6)δ11.08-10.95(m，1H)，8.77-8.67(m，1H)，8.55-8.41(m，1H)，7.64-7.48(m，1H)，7.39-7.27(m，1H)，7.05-6.94(m，1H)，3.47-3.34(m，1H)，3.11-2.99(m，2H)，2.98-2.82(m，2H)，2.61-2.57(m，3H)，2.56-2.54(m，1H)，2.18-2.13(m，3H)，2.03-1.83(m，4H)，1.39-1.26(m，6H)。
Example 5
6- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) -8-methoxy- [1, 2, 4] triazolo [1, 5-a ] pyridine dihydrochloride
Figure BDA0001979596660001532
At room temperature to 4- (3-isopropyl-2- (8-methoxy- [1, 2, 4)]Triazolo [1, 5-a]To a stirred suspension of pyridin-6-yl) -1H-indol-5-yl) piperidine-1-carboxylic acid tert-butyl ester (46.5g, 95mmol) in DCM (47.5mL) and MeOH (190mL) was added 4M HCl in dioxane (119mL, 475 mmol). After 1h, the clear solution turned into a white suspension. MeOH (50mL) was added and the suspension was stirred for an additional 1 hour. The reaction mixture was concentrated under reduced pressure and then diluted with ether (300 mL). The desired product, HCl salt, was collected by filtration and dried for two days to give 6- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) -8-methoxy- [1, 2, 4 as an off-white solid]Triazolo [1, 5-a]Pyridine dihydrochloride (33.6g, 72.7mmol, 76% yield). LCMS MH+: 390.1. HPLC retention time 0.64 min. Method G.
Example 7
2- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -N-methylacetamide
Figure BDA0001979596660001541
To 6- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) -8-methyl- [1, 2, 4]Triazolo [1, 5-a]To a solution of pyridine (2.6g, 6.96mmol) in THF (50mL) were added triethylamine (9.70mL, 69.6mmol) and 2-chloro-N-methylacetamide (2.246g, 20.88 mmol). The reaction mixture was stirred at room temperature for 12 h. The reaction mass was concentrated in vacuo and the resulting residue quenched with 150mL of ice-cold water to give a precipitate. The solid was collected by vacuum filtration and air dried. The collected solid was further dried in vacuo for 15h to give 2- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4) as an off-white solid ]Triazolo [1, 5-a]Pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -N-methylacetamide (1.5 g).1H NMR(400MHz，DMSO-d6)δ1.42(d，J＝7.20Hz，6H)，1.69-1.72(m，4H)，1.75-1.81(m，1H)，2.78-2.82(m，6H)，2.85-2.88(m，4H)，3.25-3.31(m，2H)，7.05(dd，J＝1.60，8.40Hz，1H)，7.31(d，J＝8.40Hz，1H)，7.59(d，J＝10.00Hz，2H)，7.72-7.73(m，1H)，8.54(s，1H)，8.81(s，1H)，11.12(s，1H). Molecular formula C26H32N6LCMS for O is 444.264; measured value 445 (M)+). Waters Xbridge C18, 19X 150mm, 5 μm; protection of the column: waters Xbridge C18, 19X 10mm, 5 μm; mobile phase A: 5: 95 acetonitrile: water +10mM NH4OAc; mobile phase B: 95: 5 acetonitrile: water +10mM NH4OAc; gradient: 10-50% B over 25 minutes, then 10 minutes at 50% B and 5 minutes at 100% B; flow rate: 15 mL/min; rt min: 1.91; wavelength: 220 nm. HPLC: XBridge Phenyl (4.6 × 150) mm, 3.5 μm SC/749, buffer: 0.05% TFA in water pH 2.5, mobile phase a: buffer: ACN (95: 5), mobile phase B: ACN buffer (95: 5), flow rate: 1mL \ min, time B%: 010, 12100, 15100. Retention time 6.19 minutes.
The following examples were prepared according to the general procedure disclosed in example 7.
TABLE 4
Figure BDA0001979596660001542
Figure BDA0001979596660001551
Figure BDA0001979596660001561
Figure BDA0001979596660001571
Example 13
2- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) acetonitrile
Figure BDA0001979596660001572
Into a 1 dram vialAdding 6- (3-isopropyl-5- (piperidine-4-yl) -1H-indol-2-yl) -7, 8-dimethyl- [1, 2, 4%]Triazolo [1, 5-a ]Pyridine hydrochloride (0.050g, 0.118mmol), NMP and DBU (0.025ml, 0.164 mmol). The material was brought into solution and 2-bromoacetonitrile (0.014g, 0.118mmol) was added. The reaction vial was capped. The reaction mixture was stirred at room temperature overnight. Solvent for sample (90: 10: 0.1 CH)3CN: water: TFA), filtered and purified with preparative HLPC. The crude material was purified via preparative LC/MS using the following conditions: column: XBridge C18, 19 × 200mm, 5 μm particles; mobile phase A: 5: 95 acetonitrile: water +10mM ammonium acetate; mobile phase B: 95: 5 acetonitrile: water +10mM ammonium acetate; gradient: 30-70% B over 20 minutes, followed by 5 minutes at 100% B; flow rate: 20 mL/min. The fractions containing the desired product were combined and dried by centrifugal evaporation to give 2- (4- (2- (7, 8-dimethyl- [1, 2, 4)]Triazolo [1, 5-a]Pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) acetonitrile (16.8mg, 0.039mmol, 32.7% yield). LCMS MH+: 427.1. HPLC retention time 1.30 min. Method QC-ACN-TFA-XB.1H NMR(500MHz，DMSO-d6)δ8.77-8.69(m，1H)，8.50-8.35(m，1H)，7.61-7.51(m，1H)，7.33-7.23(m，1H)，7.08-6.93(m，1H)，3.44-3.34(m，1H)，2.98-2.83(m，3H)，2.63-2.56(m，4H)，2.56-2.53(m，2H)，2.39-2.28(m，2H)，2.21-2.12(m，3H)，1.90-1.69(m，4H)，1.37-1.26(m，6H)。
Example 15
2- (4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) acetamide
Figure BDA0001979596660001573
To the reaction flask was added 6- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) -7, 8-dimethyl- [1, 2, 4% ]Triazolo [1, 5-a]Pyridine 2HCl (47.66g, 104mmol), DCE (220mL), DBU (62.4mL, 414mmol), and 2-bromoacetamide (17.14g, 124 mmol). The reaction flask was capped. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated, diluted with water and stirredFor 30 minutes, followed by filtration. The solid was recrystallized from ethanol to give 2- (4- (2- (7, 8-dimethyl- [1, 2, 4) as a white solid]Triazolo [1, 5-a]Pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) acetamide (42.3g, 93mmol, 90% yield). LCMS MH+: 445. HPLC retention time 1.20 min. Method QC-ACN-TFA-XB.1H NMR(400MHz，DMSO-d6)δ10.97-10.86(m，1H)，8.78-8.69(m，1H)，8.54-8.40(m，1H)，7.64-7.49(m，1H)，7.30-7.21(m，2H)，7.17-7.09(m，1H)，7.06-6.93(m，1H)，2.99-2.82(m，5H)，2.62-2.54(m，4H)，2.24-2.12(m，5H)，1.92-1.72(m，4H)，1.37-1.29(m，6H)。
Example 18
6- (3-isopropyl-5- (1- (2- (methylsulfonyl) ethyl) piperidin-4-yl) -1H-indol-2-yl) -7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridine
Figure BDA0001979596660001581
Preparation 1:
to a 40ml vial was added 6- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) -7, 8-dimethyl- [1, 2, 4%]Triazolo [1, 5-a]Pyridine (0.800g, 2.064mmol), DCM (5mL) and DBU (0.622mL, 4.13 mmol). The material became a solution and 2-bromoacetamide (0.299g, 2.168mmol) was added. The reaction vial was capped. The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with water and extracted with DCM. The organics were washed with brine, over Na 2SO4Dried, filtered and concentrated. The residue was dissolved in minimal DCM and purified by silica gel chromatography eluting with 0-10% MeOH in DCM. After concentration of the fractions, the product was collected as a white solid (0.6 g). To this was added 40mL of a 10% MeOH in ethyl acetate solution and the suspension was boiled. The solid was filtered off and washed with hot MeOH/ethyl acetate (1: 10). The filtrate was heated again and capped for recrystallization. After 3 days, the white solid was filtered off and washed with ethyl acetate and then with diethyl ether and dried on a vacuum pump overnight to give 2- (4- (2- (7, 8-dimethyl- [1, 2, 4)]Triazolo [1, 5-a]Pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidine-1-yl) acetamide (480mg, 1.07mmol, 51.8% yield). MS (M)+1)m/z：445.3(MH+). LC retention time 0.69 min. [ G ]]。1H NMR(400MHz，DMSO-d6)δ11.00-10.85(m，1H)，8.79-8.69(m，1H)，8.53-8.43(m，1H)，7.60-7.49(m，1H)，7.32-7.21(m，2H)，7.18-7.11(m，1H)，7.06-6.99(m，1H)，3.00-2.83(m，5H)，2.63-2.55(m，4H)，2.24-2.12(m，5H)，1.92-1.72(m，4H)，1.40-1.24(m，6H)。
Preparation 2:
to the reaction vial was added 6- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) -7, 8-dimethyl- [1, 2, 4-]Triazolo [1, 5-a]Pyridine 2HCl (40g, 87mmol), DCE (280mL), and DBU (45.8mL, 304 mmol). The material was brought into solution and 1-bromo-2- (methylsulfonyl) ethane (18.46g, 99mmol) was added. The reaction mixture was heated at room temperature under N2Stirring was continued overnight. The sample was concentrated, diluted with water, stirred for 30 minutes and then filtered. Recrystallization of the solid from EtOH gave 6- (3-isopropyl-5- (1- (2- (methylsulfonyl) ethyl) piperidin-4-yl) -1H-indol-2-yl) -7, 8-dimethyl- [1, 2, 4-dimethyl ] -as a white solid ]Triazolo [1, 5-a]Pyridine (40g, 81mmol, 93% yield). LCMS MH+: 494.3. HPLC retention time 1.70 min. Method QC-ACN-AA-XB.1H NMR (400MHz, chloroform-d) Δ 8.45-8.38(m, 1H), 8.37-8.30(m, 1H), 8.18-8.12(m, 1H), 7.69-7.62(m, 1H), 7.43-7.35(m, 1H), 7.19-7.12(m, 1H), 3.29-3.20(m, 2H), 3.16-3.07(m, 5H), 3.02-2.92(m, 3H), 2.74-2.67(m, 1H), 2.66-2.60(m, 3H), 2.31-2.22(m, 2H), 2.21-2.17(m, 3H), 2.07-1.79(m, 4H), 1.42-1.35(m, 6H).
Example 25
2- (4- (3-isopropyl-2- (8-methoxy- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -N, N-dimethylacetamide
Figure BDA0001979596660001591
Preparation 1:
to 6- (3-isopropyl-5- (piperidin-4-yl) -1H-indole at room temperatureIndole-2-yl) -8-methoxy- [1, 2, 4]Triazolo [1, 5-a]To a solution of pyridine (0.05g, 0.128mmol) in a solvent mixture of THF (2mL) and DMF (1mL) was added 2-chloro-N, N-dimethylacetamide (0.023g, 0.193mmol) and TEA (0.179mL, 1.284 mmol). The reaction mixture was stirred at room temperature for 24 h. The reaction mixture was concentrated in vacuo. Water (5mL) was added to the solid material and extracted with ethyl acetate. The organic layer was washed with Na2SO4Dried, filtered and concentrated in vacuo. The crude material was purified via preparative LC/MS using the following conditions: column: waters XBridge C18, 19 × 150mm, 5 μm particles; mobile phase A: 10mM ammonium acetate; mobile phase B: methanol; gradient: 10-50% B over 30 minutes, followed by 5 minutes at 100% B; flow rate: 15 mL/min. The product-containing fractions were combined and dried by centrifugal evaporation to give 2- (4- (3-isopropyl-2- (8-methoxy- [1, 2, 4) ]Triazolo [1, 5-a]Pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -N, N-dimethylacetamide (14.2mg, 0.03mmol, 23.31% yield). MS (M)+1)m/z：475.4(MH+). LC retention time 1.38 min. [ A ]]。1H NMR(400MHz，DMSO-d6)δ11.38(s，1H)，8.83-8.75(m，2H)，7.83(s，1H)，7.57(d，J＝8.3Hz，1H)，7.41(d，J＝1.2Hz，1H)，7.30(dd，J＝8.4，1.6Hz，1H)，4.34(s，3H)，3.43(d，J＝5.9Hz，3H)，3.34(s，4H)，3.22(d，J＝11.0Hz，4H)，3.09(s，3H)，2.79(d，J＝1.7Hz，3H)，2.48-2.38(m，2H)，2.15(s，5H)，2.08-1.95(m，4H)，1.72(d，J＝7.1Hz，6H)。
Preparation 2:
to 6- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) -8-methoxy- [1, 2, 4 at room temperature]Triazolo [1, 5-a]To a solution of pyridine HCl (30.6g, 71.8mmol) in DMF (700mL) solvent mixture was added 2-chloro-N, N-dimethylacetamide (9.62mL, 93mmol) and TEA (50.1mL, 359 mmol). The reaction mixture was stirred at room temperature for 12 h. The starting material is converted into the product. Then, water (2L) was added to the above solution, and the upper layer and the lower layer were extracted with ethyl acetate. The combined organic layers were washed with brine, dried and concentrated to give a solid which was purified by recrystallization from ethanol to give 2- (4- (3-isopropyl-2- (8-methoxy- [1, 2, 4)]Triazolo [1, 5-a]Pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -N, N-dimethylacetamide (28.3g, 59.3mmol, 83% yield). LCMS MH+: 475.2. HPLC retention time 0.66 min. Method G. C: 68.28%, H: 7.19%, N: 17.63 percent.
Example 26
6- (3-isopropyl-5- (1- (oxetan-3-yl) piperidin-4-yl) -1H-indol-2-yl) -8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine
Figure BDA0001979596660001601
To 6- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) -8-methyl- [1, 2, 4]Triazolo [1, 5-a]To a solution of pyridine hydrochloride (24.5g, 59.8mmol) in DCM (610mL) was added triethylamine (24.19g, 239mmol), oxetan-3-one (17.23g, 239mmol), acetic acid (7.18g, 120mmol) and sodium triacetoxyborohydride (50.7g, 239 mmol). The solution was stirred at room temperature. After 5min, LCMS showed 20% conversion; after overnight HPLC showed no starting material. The solvent was removed in vacuo. The residue was dissolved in 500mL ethyl acetate and saturated NaHCO3The solution (4X 300mL) was washed with Na2SO4Dried and concentrated under reduced pressure. The residue was purified by recrystallization from a mixture of EtOH/water (20/80) and dried to give 6- (3-isopropyl-5- (1- (oxetan-3-yl) piperidin-4-yl) -1H-indol-2-yl) -8-methyl- [1, 2, 4) as a white solid]Triazolo [1, 5-a]Pyridine (24.6g, 57.0mmol, 95% yield). LCMS MH+430.1. The retention time was 0.63 min. Column: BEH C182.1X 50mm 1.7. mu.m. Vial: 3: 1. HPLC retention time 7.86 min. Waters XSelect CSH C182.5 μm 4.6. mu. m.times.7.5 mm. Solvent A: h2O w/0.1% TFA. Solvent B: ACN w/0.1% TFA. Gradient composition start% B10% 16min 45% B20min 90% 24min 90% 25min 10% stop time 25 min. Flow rate: 1.5 mL/min. 1H NMR(500MHz，DMSO-d6)δ11.11(s，1H)，8.75(s，1H)，8.51(s，1H)，7.56(d，J＝16.5Hz，2H)，7.30(d，J＝8.4Hz，1H)，7.03(d，J＝8.3Hz，1H)，4.64-4.33(m，4H)，4.72-4.27(m，4H)，3.65(br.s.，2H)，3.47-3.12(m，2H)，2.79(d，J＝10.4Hz，2H)，2.61(s，3H)，1.99-1.59(m，7H)，1.41(d，J＝6.8Hz，6H)。
Alternative preparation of example 26:
to 6- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) -8-methyl- [1, 2, 4]Triazolo [1, 5-a]To a solution of pyridine hydrochloride (24.5g, 59.8mmol) in DCM (610ml) were added triethylamine (24.19g, 239mmol), oxetan-3-one (17.23g, 239mmol), acetic acid (7.18g, 120mmol) and sodium triacetoxyborohydride (50.7g, 239 mmol). The solution was stirred at room temperature and the reaction was allowed to progress 20% after 5 min. The reaction was completed overnight. The solvent was removed under reduced pressure. The residue was dissolved in 500mL ethyl acetate and saturated NaHCO3The solution (300 mL. times.4) was washed with Na2SO4Dried and concentrated under reduced pressure to give the crude product. The crude material was purified in the following work-up to remove Pd and recrystallized from a mixture of EtOH/water (20/80) and dried to give 6- (3-isopropyl-5- (1- (oxetan-3-yl) piperidin-4-yl) -1H-indol-2-yl) -8-methyl- [1, 2, 4-methyl ] indole as a solid]Triazolo [1, 5-a]Pyridine (24.6g, 57.0mmol, 95% yield). LCMS MH+: 430.1. HPLC retention time 0.63 min. Method G.1H NMR(400MHz，DMSO-d6)δ11.18-11.05(m，1H)，8.88-8.76(m，1H)，8.58-8.47(m，1H)，7.64-7.54(m，2H)，7.34-7.26(m，1H)，7.09-6.96(m，1H)，4.61-4.53(m，2H)，4.51-4.42(m，2H)，3.48-3.37(m，1H)，3.31-3.20(m，1H)，2.86-2.78(m，2H)，2.68-2.63(m，3H)，2.63-2.55(m，1H)，1.96-1.68(m，6H)，1.49-1.38(m，6H)。
Pd removal procedure: the sample was treated to remove Pd using the following steps: 1. the crude sample was dissolved in 500mL THF and treated with SilicaMetS @ DMT (40g from SiliCycle). The solution was incubated at room temperature under N 2Stirring was continued overnight. 2. After filtration, the solvent was removed and the residue was dissolved in AcOEt and washed with brine and dried. 3. After concentration, the residue was recrystallized from EtOH-water (20/80) to give the product.
The following examples were prepared according to the general procedure of example 26.
TABLE 5
Figure BDA0001979596660001621
Figure BDA0001979596660001631
Figure BDA0001979596660001641
Example 44
6- (3-isopropyl-5- (1- (oxetan-3-yl) piperidin-4-yl) -1H-indol-2-yl) -8-methoxy- [1, 2, 4] triazolo [1, 5-a ] pyridine
Figure BDA0001979596660001642
To 6- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) -8-methoxy- [1, 2, 4]Triazolo [1, 5-a]To a solution of pyridine dihydrochloride (39.7g, 86mmol) in DCM (859ml) were added triethylamine (34.8g, 343mmol), oxetan-3-one (24.75g, 343mmol), acetic acid (10.31g, 172mmol) and sodium triacetoxyborohydride (72.8g, 343 mmol). The solution was stirred at room temperature. After 9h, no more starting material was detected. The solvent was removed by rotary evaporator. The residue was dissolved in 1500mL ethyl acetate and saturated NaHCO3The solution (500 mL. times.4) was washed with Na2SO4Dried and concentrated under reduced pressure to give a residue. The residue was purified by recrystallization twice from a mixture of EtOH/water (60/40) and dried to give 6- (3-isopropyl-5- (1- (oxetan-3-yl) piperidin-4-yl) -1H-indol-2-yl) -8-methoxy- [1, 2, 4 as a white solid ]Triazolo [1, 5-a]Pyridine (32.3g, 72.2mmol, 84% yield). LCMS MH+: 446.1. HPLC retention time 0.63 min. Method G.1H NMR (400MHz, chloroform-d) Δ 8.42-8.31(m, 2H), 8.20-8.10(m, 1H), 7.77-7.67(m, 1H), 7.44-7.36(m, 1H), 7.31-7.26(m, 1H), 7.21-7.12(m, 1H), 6.95-6.85(m, 1H), 4.80-4.63(m, 4H), 4.12-4.03(m, 3H), 3.62-3.51(m, 1H), 3.42-3.25(m,1H)，3.02-2.87(m，2H)，2.73-2.58(m，1H)，2.10-1.85(m，6H)，1.55-1.44(m，6H)。
example 46
2- (dimethylamino) -1- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) ethan-1-one
Figure BDA0001979596660001651
To 6- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) -8-methyl- [1, 2, 4]Triazolo [1, 5-a]To a solution of pyridine (75mg, 0.201mmol) in DMF (1mL) were added TEA (0.140mL, 1.004mmol), 2- (dimethylamino) acetic acid (20.71mg, 0.201mmol) and HATU (76mg, 0.201 mmol). The reaction mixture was stirred at room temperature for 12 h. The reaction mass was diluted with methanol (2mL) and passed through a syringe pad to filter out inorganic material and then purified by reverse phase preparative chromatography. The crude material was purified via preparative LC/MS using the following conditions: column: waters XBridge C18, 19 × 150mm, 5 μm particles; mobile phase A: 10mM ammonium acetate; mobile phase B: acetonitrile; gradient: 20-60% B over 30 minutes, followed by 5 minutes at 100% B; flow rate: 15 mL/min. The fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 11.7mg and its purity, assessed by LCMS analysis, was 96%. Two analytical LC/MS injections were used to determine the final purity. Injection 1 conditions: column: ascentis Express C18 (50X 2.1) mm, 2.7 μm; mobile phase A: 5: 95 acetonitrile: water +10mM NH 4OAc; mobile phase B: 95: 5 acetonitrile: water +10mM NH4OAc; temperature: 50 ℃; gradient: 0-100% B over 3 minutes; flow rate: 1.1 mL/min. Injection 2 conditions: column: ascentis Express C18 (50X 2.1) mm, 2.7 μm; mobile phase A: 5: 95 acetonitrile: water + 0.1% TFA; mobile phase B: 95: 5 acetonitrile: water + 0.1% TFA; temperature: 50 ℃; gradient: 0-100% B over 3 minutes; flow rate: 1.1 mL/min.1H-NMR(400MHz，DMSO-d6)：δ1.12(d，J＝6.00Hz，3H)，1.44(d，J＝6.80Hz，6H)，1.69-1.72(m，2H)，1.75-1.81(m，2H)，2.32-2.34(m，1H)，2.50(s，3H)，2.62-2.71(m，4H)，2.80-2.94(m，1H)，3.25-3.32(m, 2H), 3.54-3.58(m, 2H), 4.00-4.07(m, 1H), 4.60(d, J ═ 11.20Hz, 1H), 7.04(dd, J ═ 1.20, 8.40Hz, 1H), 7.30(d, J ═ 8.40Hz, 1H), 7.58(d, J ═ 8.80Hz, 1H), 8.53(s, 1H), 8.80(s, 1H), 11.11(s, 1H). Molecular formula C26H32N6LCMS for O is 444.264; measured value 445 (M)+). Waters Xbridge C18, 19X 150mm, 5 μm; protection of the column: waters Xbridge C18, 19X 10mm, 5 μm; mobile phase A: 5: 95 acetonitrile: water +10mM NH4OAc; mobile phase B: 95: 5 acetonitrile: water +10mM NH4OAc; gradient: 10-50% B over 25 minutes, then 10 minutes at 50% B and 5 minutes at 100% B; flow rate: 15 mL/min; rt min: 1.91; wavelength: 220 nm.
Example 47
1- (4- (2- ([1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -2- (methylamino) ethan-1-one
Figure BDA0001979596660001661
To a 1 dram vial was added 6- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) - [1, 2, 4%]Triazolo [1, 5-a]Pyridine (0.035g, 0.091mmol), CH3CN, TEA (0.038mL, 0.273mmol) and HATU (0.036g, 0.091 mmol). The material turned into solution and 2- ((tert-butoxycarbonyl) (methyl) amino) acetic acid (0.034g, 0.182mmol) was added. The reaction vial was capped and stirred at room temperature overnight. After 18h, LC-MS showed that the product had formed. The sample was diluted with ethyl acetate and washed with water. The combined organics were washed with brine, over Na2SO4Dried, filtered and concentrated. To this was added 1mL of DCM and 1mL of 4M HCl in dioxane. The reaction mixture was stirred at room temperature for 30 minutes, concentrated, and washed with solvent B (90: 10: 0.1 CH)3CN: water: TFA), filtered and purified by preparative reverse phase chromatography. The crude material was purified via preparative LC/MS using the following conditions: column: XBridge C18, 19 × 200mm, 5 μm particles; mobile phase A: 5: 95 acetonitrile: water +10mM ammonium acetate; mobile phase B: 95: 5 acetonitrile: water +10mM ammonium acetate; ladder with adjustable heightDegree: 10-50% B over 20 minutes, followed by 5 minutes at 100% B; flow rate: 20 mL/min. The fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 7.4mg and its purity assessed by LCMS analysis was 96%. Two analytical LC/MS injections were used to determine the final purity. Injection 1 conditions: column: WatersAcquity UPLC BEH C18, 2.1X 50mm, 1.7 μm particle; mobile phase A: 5: 95 acetonitrile: water +10mM ammonium acetate; mobile phase B: 95: 5 acetonitrile: water +10mM ammonium acetate; temperature: 50 ℃; gradient: 0-100% B over 3 minutes, then held at 100% B for 0.75 minutes; flow rate: 1.0 mL/min; and (3) detection: UV 220 nm. Injection 2 conditions: column: waters Acquity UPLC BEH C18, 2.1X 50mm, 1.7 μm particles; mobile phase A: 5: 95 acetonitrile: water + 0.1% trifluoroacetic acid; mobile phase B: 95: 5 acetonitrile: water + 0.1% trifluoroacetic acid; temperature: 50 ℃; gradient: 0-100% B over 3 minutes, then held at 100% B for 0.75 minutes; flow rate: 1.0 mL/min; and (3) detection: UV 220 nm. Proton NMR was obtained in deuterated DMSO. LC-MS: m +1 is 431. Rt 1.127 min. [ D1 ]. Proton NMR was obtained in deuterated DMSO.1H NMR(500MHz，DMSO-d6)δ11.19(s，1H)，8.97(s，1H)，8.58(s，1H)，7.98(d，J＝9.2Hz，1H)，7.79(d，J＝10.4Hz，1H)，7.56(s，1H)，7.33(d，J＝8.3Hz，1H)，7.03(d，J＝8.8Hz，1H)，4.55(d，J＝13.0Hz，1H)，3.88(d，J＝13.2Hz，1H)，3.58(s，1H)，3.33-3.21(m，1H)，3.16-3.06(m，1H)，2.88(d，J＝7.5Hz，2H)，2.77-2.63(m，2H)，2.38(s，5H)，1.73-1.59(m，2H)，1.43(d，J＝7.0Hz，6H)。
The following examples were prepared according to the general methods disclosed in examples 46 or 47.
TABLE 6
Figure BDA0001979596660001671
Figure BDA0001979596660001681
Figure BDA0001979596660001691
Example 68
1- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -2-morpholinoethan-1-one
Figure BDA0001979596660001701
Mixing 6- (3-isopropyl-5- (piperidine-4-yl) -1H-indol-2-yl) -8-methyl- [1, 2, 4]Triazolo [1, 5-a]Pyridine hydrochloride (0.250g, 0.610mmol) was dissolved in NMP (5 mL). Et was added sequentially3N (0.255mL, 1.829mmol) and 2-chloroacetyl chloride (0.073mL, 0.915 mmol). The reaction was monitored by LCMS. After stirring for 1.5 hours, the reaction mixture was diluted with NMP and used as a solution for the next step.
2-chloro-1- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) ethanone (0.035g, 0.078mmol) was dissolved in NMP (1 mL). DBU (0.059mL, 0.389mmol) and morpholine (0.020mL, 0.233mmol) were added sequentially. The reaction was monitored by LCMS. The reaction mixture was stirred overnight. The reaction mixture was diluted with solvent (90: 10 ACN: water, 0.1% TFA) and the crude material was purified via preparative LC/MS using the following conditions: column: XBridge C18, 19 × 200mm, 5 μm particles; mobile phase A: 5: 95 acetonitrile: water + 0.1% trifluoroacetic acid; mobile phase B: 95: 5 acetonitrile: water + 0.1% trifluoroacetic acid; gradient: 10-50% B over 30 minutes, followed by 5 minutes at 100% B; flow rate: 20 mL/min. The product-containing fractions were combined and dried via centrifugal evaporation.
The yield of the product was 37.9mg and its purity, as assessed by LCMS analysis, was 100%. Two analytical LC/MS injections were used to determine the final purity. Injection 1 conditions: column: waters Acquity UPLC BEH C18, 2.1X 50mm, 1.7 μm particles; mobile phase A: 5: 95 acetonitrile: water +10mM ammonium acetate; mobile phase B: 95: 5 acetonitrile: water +10mM ammonium acetate; temperature: 50 ℃; gradient: 0-100% B over 3 minutes, then held at 100% B for 0.75 minutes; flow rate: 1.0 mL/min; detection ofAnd (3) measurement: UV 220 nm. Injection 2 conditions: column: WatersAcquity UPLC BEH C18, 2.1X 50mm, 1.7 μm particle; mobile phase A: 5: 95 acetonitrile: water + 0.1% trifluoroacetic acid; mobile phase B: 95: 5 acetonitrile: water + 0.1% trifluoroacetic acid; temperature: 50 ℃; gradient: 0-100% B over 3 minutes, then held at 100% B for 0.75 minutes; flow rate: 1.0 mL/min; and (3) detection: UV 220 nm. LC-MS: m +1 is 501. Rt is 1.157 min. [ D1]. Proton NMR was obtained in deuterated DMSO.1H NMR(400MHz，DMSO-d6)δ＝11.12(s，1H)，8.79(d，J＝0.8Hz，1H)，8.53(s，1H)，7.59(d，J＝6.4Hz，2H)，7.29(d，J＝8.4Hz，1H)，7.02(dd，J＝8.4，1.2Hz，1H)，4.88-4.82(m，2H)，4.52-4.48(m，1H)，4.28-4.22(m，2H)，4.09-4.04(m，1H)，3.28-3.21(m，1H)，3.19-3.02(m，6H)，2.85-2.76(m，1H)，2.68-2.59(m，2H)，2.58(s，3H)，1.88-1.80(m，2H)，1.69-1.50(m，2H)，1.43(d，J＝7.2Hz，6H)。
The following examples were prepared in accordance with the general procedure disclosed in example 68.
TABLE 7
Figure BDA0001979596660001711
Example 74
1- (1, 1-dioxo-1, 2, 4-thiadiazinan-4-yl) -2- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) ethan-1-one
Figure BDA0001979596660001712
Intermediate 74A: 2- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) acetic acid
Figure BDA0001979596660001721
6- (3-isopropyl-5- (piperidin-4-yl) -1H in glass vials-indol-2-yl) -8-methyl- [1, 2, 4]Triazolo [1, 5-a]Pyridine (0.580g, 1.233mmol) was dissolved in CH2Cl2(8.22mL) and N, N-diisopropylethylamine (1.074mL, 6.16 mmol). To the vial was added methyl 2-bromoacetate (0.141mL, 1.479mmol) to give a clear bright yellow solution. The reaction mixture was stirred at rt for 1.5 h. The excess solvent was evaporated from the reaction mixture under a stream of nitrogen. The material was purified by silica gel chromatography using hexane and ethyl acetate as eluents (0% to 100% ethyl acetate gradient). The product fractions were combined and evaporated to dryness. The material was dissolved in 2mL THF and 2mL MeOH and treated with 2mL 4M NaOH. Then 1mL of water was added and the mixture was stirred at 45 ℃ overnight. The mixture was diluted with water and acidified with 1N HCl to pH 5. Ethyl acetate was added and the layers were separated. The combined organics were washed with Na2SO4Drying, filtering and concentrating to obtain 2- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4))]Triazolo [1, 5-a]Pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) acetic acid.
Example 74:
to a 2 dram vial was added 2- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4))]Triazolo [1, 5-a]Pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) acetic acid (0.025g, 0.058mmol), CH3CN and TEA (0.024mL, 0.174 mmol). The sample became a solution and HATU (0.033g, 0.087mmol) was added. The reaction vial was capped and stirred at room temperature overnight. Solvent for sample (90: 10: 0.1 CH)3CN: water: TFA), filtered and subsequently purified by preparative reverse phase HPLC.
The crude material was purified via preparative LC/MS using the following conditions: column: XBridge Phenyl, 19X 200mm, 5 μm particles; mobile phase A: 5: 95 acetonitrile: water +10mM ammonium acetate; mobile phase B: 95: 5 acetonitrile: water +10mM ammonium acetate; gradient: 20-60% B over 20 minutes, followed by 5 minutes at 100% B; flow rate: 20 mL/min. The fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 0.8mg and its purity assessed by LCMS analysis was 99%. Two analytical LC/MS injections were used to determine the final purity. Injection 1 conditions: column: waters Acquity UPLC BEH C18, 2.1X 50mm, 1.7 μm particles; mobile phase A: 5: 95 acetonitrile: water +10mM ammonium acetate; mobile phase B: 95: 5 acetonitrile: water +10mM ammonium acetate; temperature: 50 ℃; gradient: 0-100% B over 3 minutes, then held at 100% B for 0.75 minutes; flow rate: 1.0 mL/min; and (3) detection: UV 220 nm. Injection 2 conditions: column: WatersAcquity UPLC BEH C18, 2.1X 50mm, 1.7 μm particle; mobile phase A: 5: 95 acetonitrile: water + 0.1% trifluoroacetic acid; mobile phase B: 95: 5 acetonitrile: water + 0.1% trifluoroacetic acid; temperature: 50 ℃; gradient: 0-100% B over 3 minutes, then held at 100% B for 0.75 minutes; flow rate: 1.0 mL/min; and (3) detection: UV 220 nm. Proton NMR was obtained in deuterated DMSO.
The following examples were prepared according to the general procedure described in example 74.
TABLE 8
Figure BDA0001979596660001731
Figure BDA0001979596660001741
Figure BDA0001979596660001751
Example 94
8-Ethyl-6- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridine
Figure BDA0001979596660001761
Intermediate 94A: 6-bromo-8-iodo- [1, 2, 4] triazolo [1, 5-a ] pyridines
Figure BDA0001979596660001762
To 6-bromo-8-iodo- [1, 2, 4]Triazolo [1, 5-a]To a stirred solution of pyridine (100mg, 0.309mmol) in EtOH (20mL) was added vinylboronPinacol acid ester (62.0mg, 0.463 mmol). Using N2The mixture was degassed for 10 min. Then PdCl is added2(dppf)-CH2Cl2(12.61mg, 0.015mmol) and Et3N (0.129mL, 0.926mmol) and the reaction mixture was heated to 80 ℃ and held for 16 h. The reaction mixture was filtered through a pad of celite, washed with EtOAc and the organic layer was concentrated to give 6-bromo-8-vinyl- [1, 2, 4]Triazolo [1, 5-a]Pyridine (70mg, 95%). LC retention time 1.0.4 min. [ K ]]。MS(E-)m/z：226(M+H)。
Intermediate 94B: 4- (3-isopropyl-2- (8-vinyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidine-1-carboxylic acid tert-butyl ester
Figure BDA0001979596660001763
To a mixture of tert-butyl 4- (3-isopropyl-2- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-indol-5-yl) piperidine-1-carboxylate (300mg, 0.640mmol) and 6-bromo-8-vinyl- [1, 2, 4 mmol ]Triazolo [1, 5-a]To a stirred solution of pyridine (215mg, 0.961mmol) in dioxane (15mL) and water (2mL) was added potassium phosphate (408mg, 1.921 mmol). N for the mixture2Degassing for 10 min. Then PdCl is added2(dppf) (46.9mg, 0.064mmol) and the mixture degassed for 10 min. The reaction mixture was heated to 80 ℃ and held for 16 h. The reaction was filtered through a pad of celite, washed with EtOAc and concentrated to give 4- (3-isopropyl-2- (8-vinyl- [1, 2, 4)]Triazolo [1, 5-a]Pyridin-6-yl) -1H-indol-5-yl) piperidine-1-carboxylic acid tert-butyl ester. The crude material was purified by silica gel chromatography to give 4- (3-isopropyl-2- (8-vinyl- [1, 2, 4] as a white solid]Triazolo [1, 5-a]Pyridin-6-yl) -1H-indol-5-yl) piperidine-1-carboxylic acid tert-butyl ester (230mg, 74%). LC retention time 1.74 min. [ K ]]。MS(E-)m/z：486(M+H)。
Intermediate 94C: 4- (2- (8-Ethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidine-1-carboxylic acid tert-butyl ester
Figure BDA0001979596660001771
4- (3-isopropyl-2- (8-vinyl- [1, 2, 4))]Triazolo [1, 5-a]A solution of pyridin-6-yl) -1H-indol-5-yl) piperidine-1-carboxylic acid tert-butyl ester (180mg, 0.371mmol) in ethyl acetate (15mL) was treated with nitrogen (N)2) And (5) flushing. Palladium on carbon (39.4mg, 0.371mmol)) was added and the mixture was washed with N 2Rinsing three times. Introducing hydrogen (H) into the mixture via a balloon2). The reaction mixture was stirred at rt for 5 h. The suspension was filtered through celite, and the filtrate was collected and concentrated to give crude compound. The crude product was purified by silica gel chromatography. The compound was eluted with 15% ethyl acetate in hexane, fractions were collected and concentrated to give 4- (2- (8-ethyl- [1, 2, 4) as a white solid]Triazolo [1, 5-a]Pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidine-1-carboxylic acid tert-butyl ester (150mg, 83% yield). LCMS retention time 1.70 min. [ K ]]。MS(E-)m/z：488(M+H)。
Example 94:
at ambient temperature towards 4- (2- (8-ethyl- [1, 2, 4)]Triazolo [1, 5-a]To a solution of pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidine-1-carboxylic acid tert-butyl ester (140mg, 0.287mmol) in DCM (10mL) was added 4M HCl in dioxane (3.05 μ l, 0.100 mmol). The mixture was stirred at the same temperature for 1 h. The solution was concentrated to give the crude product. The crude material was purified by preparative LCMS using the following conditions: waters Xbridge C18, 19X 150mm, 5 μm; protection of the column: waters Xbridge C18, 19X 10mm, 5 μm; mobile phase A: 5: 95 methanol: Water +10mM NH4OAc; mobile phase B: 95: 5 methanol: Water +10mM NH4OAc; gradient: 15-65% B over 25 minutes, then 10 minutes at 65% B and 5 minutes at 100% B; flow rate: 15 mL/min. The product containing fractions were combined and dried using a Genevac centrifugal evaporator to give 8-ethyl-6- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) - [1, 2, 4 ] as a white solid ]Triazolo [1, 5-a]Pyridine (5.4mg, 8.5%). LC retention time 1.38 min. [ E ]]。MS(E-)m/z：388(M+H)。
Example 95
8-isopropyl-6- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridine
Figure BDA0001979596660001781
Intermediate 95A: 6-bromo-8- (prop-1-en-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridine
Figure BDA0001979596660001782
To 6-bromo-8-iodo- [1, 2, 4]Triazolo [1, 5-a]To a stirred solution of pyridine (300mg, 0.926mmol) and 4, 4, 5, 5-tetramethyl-2- (prop-1-en-2-yl) -1, 3, 2-dioxaborolan (202mg, 1.204mmol) in dioxane (10mL) and water (0.5mL) was added potassium phosphate (590mg, 2.78 mmol). Reaction mixture with N2Degassing for 10 min. Then PdCl is added2(dppf) (67.8mg, 0.093mmol) and the reaction mixture was degassed for 10 min. The reaction mixture was heated to 80 ℃ and held for 16 h. The reaction was filtered through a pad of celite, washed with EtOAc and concentrated. Purify the crude material by silica gel chromatography using 60% EtOAc-hexanes to give 6-bromo-8- (prop-1-en-2-yl) - [1, 2, 4] as an off-white solid]Triazolo [1, 5-a]Pyridine (200mg, 0.840mmol, 91% yield). LC retention time 1.19 min. [ K ]]。MS(E-)m/z：240(M+H)。
Intermediate 95B: 4- (3-isopropyl-2- (8- (prop-1-en-2-yl) - [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidine-1-carboxylic acid tert-butyl ester
Figure BDA0001979596660001783
To tert-butyl 4- (3-isopropyl-2- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-indol-5-yl) piperidine-1-carboxylate (300mg, 0.640mmol), 6-bromo-8- (prop-1-en-2-yl) - [1, 2, 4-d]Triazolo [1, 5-a]To a stirred solution of pyridine (229mg, 0.961mmol) in dioxane (15mL) and water (2mL) was added potassium phosphate (408mg, 1.921mmol) over N2Degassing for 10min to obtain a mixture, and degassing for 10min,followed by addition of PdCl2(dppf) (46.9mg, 0.064 mmol). The reaction mixture was heated to 100 ℃ and held for 16 h. The reaction was filtered through a bed of celite, washed with EtOAc and concentrated to give the crude material. This material was purified by silica gel chromatography to give 4- (3-isopropyl-2- (8- (prop-1-en-2-yl) - [1, 2, 4]]Triazolo [1, 5-a]Pyridin-6-yl) -1H-indol-5-yl) piperidine-1-carboxylic acid tert-butyl ester. The crude material was purified by ISCO silica gel column to give 4- (3-isopropyl-2- (8- (prop-1-en-2-yl) - [1, 2, 4] as a brown liquid]Triazolo [1, 5-a]Pyridin-6-yl) -1H-indol-5-yl) piperidine-1-carboxylic acid tert-butyl ester (260mg, 81% yield). LC retention time 1.87 min. [ K ]]。MS(E-)m/z：500(M+H)。
Intermediate 95C: 4- (3-isopropyl-2- (8-isopropyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidine-1-carboxylic acid tert-butyl ester
Figure BDA0001979596660001791
4- (3-isopropyl-2- (8- (prop-1-en-2-yl) - [1, 2, 4 ]]Triazolo [1, 5-a]A solution of pyridin-6-yl) -1H-indol-5-yl) piperidine-1-carboxylic acid tert-butyl ester (180mg, 0.360mmol) in ethyl acetate (15mL) was treated with nitrogen (N)2) And (5) flushing. Palladium on carbon (38.3mg, 0.360mmol) was then added and the mixture was washed with N2Rinsing three times. Introducing hydrogen (H) into the mixture via a balloon2). The reaction mixture was stirred at rt for 5 h. The suspension was filtered through celite and the filtrate was collected and concentrated to give crude compound. The crude material was purified by silica gel chromatography and the compound was eluted with 15% ethyl acetate in hexane. Collecting multiple fractions and concentrating to obtain 4- (3-isopropyl-2- (8-isopropyl- [1, 2, 4)]Triazolo [1, 5-a]Pyridin-6-yl) -1H-indol-5-yl) piperidine-1-carboxylic acid tert-butyl ester (160mg, 89% yield). LCMS retention time 1.81 min. [ K ]]。MS(E-)m/z：502(M+H)。
Example 95:
at ambient temperature to 4- (3-isopropyl-2- (8-isopropyl- [1, 2, 4)]Triazolo [1, 5-a]Solution of pyridin-6-yl) -1H-indol-5-yl) piperidine-1-carboxylic acid tert-butyl ester (140mg, 0.279mmol) in DCM (10mL)To which was added 4M HCl in dioxane (5 mL). The mixture was stirred at the same temperature for 1 h. The solution was concentrated to give the crude product. The crude sample was purified by preparative LCMS using the following conditions: waters Xbridge C18, 19X 150mm, 5 μm; protection of the column: waters Xbridge C18, 19X 10mm, 5 μm; mobile phase A: 5: 95 methanol: Water +10mM NH 4OAc; mobile phase B: 95: 5 methanol: Water +10mM NH4OAc; gradient: 15-65% B over 25 minutes, then 10 minutes at 65% B and 5 minutes at 100% B; flow rate: 15 mL/min. The product containing fractions were combined and dried using a Genevac centrifugal evaporator to give 8-isopropyl-6- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) - [1, 2, 4] as a white solid]Triazolo [1, 5-a]Pyridine (1.5mg, 1.3%). LC retention time 1.49 min. [ E ]]。MS(E-)m/z：402(M+H)。
Example 96
8-chloro-6- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) -2-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine
Figure BDA0001979596660001801
Intermediate 96A: 4- (2- (8-chloro-2-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidine-1-carboxylic acid tert-butyl ester
Figure BDA0001979596660001802
Tert-butyl 4- (3-isopropyl-2- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-indol-5-yl) piperidine-1-carboxylate (2.0g, 4.27mmol), 6-bromo-8-chloro-2-methyl- [1, 2, 4-mmol]Triazolo [1, 5-a]A solution of pyridine (1.158g, 4.70mmol) and potassium phosphate (2.231g, 12.81mmol) in dioxane (60mL) and water (4mL) was treated with N2Degassing for 10 min. Then PdCl is added2(dppf)-CH2Cl2Adduct (0.174g, 0.213mmol) and the mixture was degassed for 5 min. The resulting reaction mixture was heated at 90 ℃ for 12 h. The reaction mixture was concentrated. Dissolving the residue in acetic acid In ethyl ester and the solution was washed with water. Collecting the organic layer, passing through Na2SO4Dried and concentrated to give crude compound. The residue was taken up in DCM (1mL) and recrystallized from petroleum ether (3X 10 mL). The resulting brown solid was filtered and dried to give 4- (2- (8-chloro-2-methyl- [1, 2, 4) as a pale yellow solid]Triazolo [1, 5-a]Pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidine-1-carboxylic acid tert-butyl ester (1.4g, 2.76mmol, 64.5%). LCMS retention time 3.74 min. [ D ]]。MS(E-)m/z：508.3(M+H)。
Example 96:
at room temperature to 4- (2- (8-chloro-2-methyl- [1, 2, 4)]Triazolo [1, 5-a]Pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidine-1-carboxylic acid tert-butyl ester (250mg, 0.492mmol) in CH2Cl2To a stirred solution in (2mL) was added TFA (0.2 mL). The reaction mixture was stirred at the same temperature for 2 h. The reaction mass was concentrated to give crude compound. The crude material was purified via preparative LC/MS using the following conditions: column: waters XBridge C18, 19 × 150mm, 5 μm particles; mobile phase A: 0.1% trifluoroacetic acid; mobile phase B: acetonitrile; gradient: 10-35% B over 25 minutes, followed by 5 minutes at 100% B; flow rate: 15 mL/min. The product containing fractions were combined and dried by centrifugal evaporation to give 8-chloro-6- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) -2-methyl- [1, 2, 4 as a pale blue solid ]Triazolo [1, 5-a]Pyridine (0.200g, 99% yield). LC retention time 2.31 min. [ E ]]。MS(E-)m/z：409.4(M+H)。1H NMR(400MHz，DMSO-d6)δppm 1.32-1.52(m，7H)1.80-1.96(m，3H)2.07(s，1H)2.28-2.40(m，1H)2.61-2.72(m，1H)2.88-3.04(m，2H)3.17(d，J＝5.02Hz，2H)3.21-3.28(m，2H)4.10(q，J＝5.02Hz，1H)7.02(dd，J＝8.53，1.51Hz，1H)7.35(d，J＝8.03Hz，1H)7.57(s，1H)，8.02(d，J＝1.51Hz，1H)8.77-8.94(m，1H)11.24(s，1H)。
Example 97
8-Ethyl-6- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) -2-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine
Figure BDA0001979596660001811
Intermediate 97A: 4- (2- (8-Ethyl-2-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidine-1-carboxylic acid tert-butyl ester
Figure BDA0001979596660001812
4- (2- (8-chloro-2-methyl- [1, 2, 4)]Triazolo [1, 5-a]Pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidine-1-carboxylic acid tert-butyl ester (0.1mg, 0.197. mu. mol), ethylboronic acid (0.015mg, 0.197. mu. mol) and dipotassium hydrogen phosphate (0.086mg, 0.492. mu. mol) in toluene (2mL) and water (0.5mL) with N2Degassing for 10 min. Then Pd (OAc) is added2(4.42. mu.g, 0.020. mu. mol) and tricyclohexylphosphine (2.76. mu.g, 0.0098. mu. mol) and the reaction mixture was degassed for 5 min. The reaction mixture was heated at 100 ℃ for 12 h. The reaction mixture was concentrated. The residue was dissolved in ethyl acetate and the solution was washed with water. Collecting the organic layer, passing through Na2SO4Drying and concentrating to obtain 4- (2- (8-ethyl-2-methyl- [1, 2, 4) light yellow solid]Triazolo [1, 5-a]Pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidine-1-carboxylic acid tert-butyl ester (80mg, 1.59mmol, 81%). LCMS retention time 3.93 min. [ D ] ]。MS(E-)m/z：502.3(M+H)。
Example 97:
to 4- (2- (8-ethyl-2-methyl- [1, 2, 4)]Triazolo [1, 5-a]To a solution of pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidine-1-carboxylic acid tert-butyl ester (0.08g, 0.159mmol) in DCM (2mL) was added dropwise 4M HCl in dioxane (0.399mL, 1.595 mmol). The reaction mixture was stirred at 25 ℃ for 1 h. The reaction mass was concentrated to give crude compound. The crude material was purified via preparative LC/MS using the following conditions: column: waters XBridge C18, 19 × 150mm, 5 μm particles; mobile phase A: 10mM ammonium acetate; mobile phase B: acetonitrile; gradient: 8-38% B over 25 minutes, followed by 5 minutes at 100% B; flow rate: 15 mL/min. The product containing fractions were combined and dried by centrifugal evaporation to give 8-ethyl-6- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl as a pale blue solid) -2-methyl- [1, 2, 4]Triazolo [1, 5-a]Pyridine (0.0013g, 2% yield). LC retention time 1.369 min. [ D1]。MS(E-)m/z：402(M+H)。1H NMR(400MHz，DMSO-d6)δppm 11.17(s，1H)，8.69(s，1H)，7.54(d，J＝18.6Hz，2H)，7.41-7.30(m，1H)，7.01(d，J＝9.0Hz，1H)，3.19-3.16(m，5H)，(3.08-2.95(m，8H)，2.08(s，1H)，1.99(d，J＝13.2Hz，6H)，1.87(d，J＝12.2Hz，7H)，1.45(d，J＝7.1Hz，9H)，1.40-1.34(m，3H)。
Example 98
4- (2- (8-Ethyl-7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidine-1-carboxylic acid tert-butyl ester
Figure BDA0001979596660001821
Intermediate 98A: 6-bromo-7-methyl-8-vinyl- [1, 2, 4] triazolo [1, 5-a ] pyridines
Figure BDA0001979596660001822
6-bromo-8-iodo-7-methyl- [1, 2, 4 [ ] ]Triazolo [1, 5-a]A solution of pyridine (0.25g, 0.740mmol) and potassium vinyltrifluoroborate (0.099g, 0.740mmol) in ethanol (5mL) was treated with N2Degassing for 10 min. Then PdCl is added2(dppf)-CH2Cl2Adduct (0.030g, 0.037mmol) and the reaction mixture was degassed for 5min before TEA (0.412mL, 2.96mmol) was added. The resulting reaction mixture was heated at 85 ℃ for 12 h. The reaction mixture was concentrated. The residue was dissolved in ethyl acetate and the solution was washed with water. Collecting the organic layer, passing through Na2SO4Drying and concentrating to obtain 6-bromo-7-methyl-8-vinyl- [1, 2, 4] as yellow solid]Triazolo [1, 5-a]Pyridine (0.25g, 0.473mmol, 63.9% yield). LCMS retention time 1.42 min. [ H ]]。MS(E-)m/z：240.3(M+2H)。
Intermediate 98B: 4- (3-isopropyl-2- (7-methyl-8-vinyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidine-1-carboxylic acid tert-butyl ester
Figure BDA0001979596660001823
Tert-butyl 4- (3-isopropyl-2- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-indol-5-yl) piperidine-1-carboxylate (0.4g, 0.854mmol), 6-bromo-7-methyl-8-vinyl- [1, 2, 4-dimethyl-1-oxo-1-methyl-8-oxo-1-carboxylic acid]Triazolo [1, 5-a]A solution of pyridine (0.224g, 0.939mmol) and potassium phosphate (0.446g, 2.56mmol) in dioxane (5mL) and water (1mL) was treated with N2Degassing for 10 min. Then PdCl is added 2(dppf)-CH2Cl2Adduct (0.035g, 0.043mmol) and the mixture was degassed again for 5 min. The resulting reaction mixture was heated at 90 ℃ for 12 h. The reaction mixture was concentrated. The residue was dissolved in ethyl acetate and the solution was washed with water. Collecting the organic layer, passing through Na2SO4Dried and concentrated to give crude compound. The residue was taken up in DCM (1mL) and recrystallized from petroleum ether (3X 10 mL). By combiflash 5% MeOH/CHCl3The crude material was purified. Concentrating the multiple fractions to obtain 4- (3-isopropyl-2- (7-methyl-8-vinyl- [1, 2, 4) -methyl-ethyl- [ 8 ] as yellow solid]Triazolo [1, 5-a]Pyridin-6-yl) -1H-indol-5-yl) piperidine-1-carboxylic acid tert-butyl ester (0.35g, 0.700mmol, 82%). LCMS retention time 3.11 min. [ D ]]。MS(E-)m/z：500.3(M+H)。
Intermediate 98C: 4- (2- (8-Ethyl-7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidine-1-carboxylic acid tert-butyl ester
Figure BDA0001979596660001831
4- (3-isopropyl-2- (7-methyl-8-vinyl- [1, 2, 4))]Triazolo [1, 5-a]A solution of pyridin-6-yl) -1H-indol-5-yl) piperidine-1-carboxylic acid tert-butyl ester (0.35g, 0.700mmol) in methanol (10mL) was treated with nitrogen (N)2) And (5) flushing. Pd/C (0.019g, 0.018mmol) was then added and the mixture was treated with N2Rinsing three times. Introducing hydrogen (H) into the mixture via a balloon 2). The reaction mixture was stirred at rt for 5 h. The suspension was filtered through a celite bed, the filtrate was collected and concentrated to give 4- (2- (8-ethyl-7-methyl- [1, 2, 4) as a white solid]Triazolo [1, 5-a]Pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidine-1-carboxylic acid tert-butyl ester (250mg, 0.498mmol, 72%). LCMS retention time 4.45 min. [ H ]]。MS(E-)m/z：502.3(M+H)。
Example 98:
to 4- (2- (8-ethyl-7-methyl- [1, 2, 4)]Triazolo [1, 5-a]Pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidine-1-carboxylic acid tert-butyl ester (0.25g, 0.498mmol) in DCM (2mL) was added dropwise 4M HCl in dioxane (0.249mL, 0.997 mmol). The reaction mixture was stirred at 25 ℃ for 1 h. The crude material was purified via preparative LC/MS using the following conditions: column: waters XBridge C18, 19 × 150mm, 5 μm particles; mobile phase A: 10mM ammonium acetate; mobile phase B: methanol; gradient: 20-60% B over 20 minutes, followed by 5 minutes at 100% B; flow rate: 15 mL/min. The product containing fractions were combined and dried by centrifugal evaporation to give 8-ethyl-6- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) -7-methyl- [1, 2, 4 as a pale blue solid]Triazolo [1, 5-a]Pyridine (180mg, 90%). LCMS retention time 1.368 min. [ E ] ]。MS(E-)m/z：402.2(M+H)。
The following examples were prepared according to the general procedures disclosed in examples 1 and 2.
TABLE 9
Figure BDA0001979596660001841
Figure BDA0001979596660001851
Figure BDA0001979596660001861
Watch 10
Figure BDA0001979596660001862
Figure BDA0001979596660001871
Figure BDA0001979596660001881
Figure BDA0001979596660001891
Figure BDA0001979596660001901
Example 161
6- (3- (2, 2-difluoroethyl) -5- (piperidin-4-yl) -1H-indol-2-yl) -8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine
Figure BDA0001979596660001902
Intermediate 161A: 5-bromo-1-tosyl-1H-indole
Figure BDA0001979596660001903
To a stirred solution of 5-bromo-1H-indole (5.0g, 25.5mmol), TsCl (6.03g, 31.6mmol) and tetrabutylammonium hydrogen sulfate (0.63g, 1.855mmol) in toluene (100mL) was added dropwise NaOH (50% in water, 10.20g, 255 mmol). The reaction mixture was stirred at rt for 16 h. The reaction was quenched with water (20 mL). The layers were separated, the aqueous layer was extracted with EtOAc (2X 50mL), and the combined organic extracts were dried (Na)2SO4) And concentrated to give the crude material. The crude material was purified by silica gel chromatography. The compound was eluted with 4% EA in hexane, fractions were collected and concentratedThis gave 5-bromo-1-tosyl-1H-indole (7.1g, 20.27mmol) as a white solid. LC retention time 2.230 min. [ A ]]。MS(E-)m/z：393.3(M-H)。
Intermediate 161B: 1- (5-bromo-1-tosyl-1H-indol-3-yl) -2, 2-difluoroethan-1-one
Figure BDA0001979596660001911
To AlCl3(6.85g, 51.4mmol) to a suspension in DCM (50mL) was added difluoroacetic anhydride (4.47g, 25.7 mmol). The reaction mixture was stirred for 15min, then a solution of 5-bromo-1-tosyl-1H-indole (3g, 8.57mmol)) in DCM (30mL) was added. The reaction mixture was stirred at ambient temperature for 1 h. The reaction was quenched with ice water. The mixture was extracted with DCM (2X 50mL) and the combined extracts were extracted with NaHCO 3Aqueous, brine, over MgSO4Dried, filtered and concentrated to give the crude material. The crude material was purified by silica gel chromatography, the compound was eluted with 10% EtOAc in hexanes, the fractions were collected and concentrated to give 1- (5-bromo-1-tosyl-1H-indol-3-yl) -2, 2-difluoroethanone (2.21g, 4.1mmol) as a crystalline solid. LC retention time 2.732 min. [ A ]]。MS(E-)m/z：428.0(M+H)。
Intermediate 161C: 1- (5-bromo-1H-indol-3-yl) -2, 2-difluoroethan-1-one
Figure BDA0001979596660001912
To a solution of 1- (5-bromo-1-tosyl-1H-indol-3-yl) -2, 2-difluoroethanone (0.2g, 0.467mmol) in a solvent mixture of THF (4mL) and MeOH (4.00mL) at room temperature was added Cs2CO3(0.45g, 1.381 mmol). The mixture was stirred at room temperature for 12 h. The reaction mixture was concentrated, the residue diluted with a minimum amount of water and the undissolved solid filtered and dried in vacuo to give 1- (5-bromo-1H-indol-3-yl) -2, 2-difluoroethanone (105mg, 0.244mmol) as a white solid. LC retention time 2.233 min. [ A ]]。MS(E-)m/z：276(M+2H)。
Intermediate 161D: 5-bromo-3- (2, 2-difluoroethyl) -1H-indole
Figure BDA0001979596660001913
To a stirred solution of 1- (5-bromo-1H-indol-3-yl) -2, 2-difluoroethanone (0.25g, 0.912mmol) in THF (10mL) at 0 deg.C under nitrogen was added BH3DMS (1.368mL, 2.74 mmol). The reaction mixture was stirred at 80 ℃ for 20 h. The reaction was quenched with water (2mL) at 0 ℃. The reaction mixture was diluted with ethyl acetate (100mL), washed with sodium bicarbonate (2 × 25mL) and water (2 × 25mL), and the combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated to give crude compound. The crude material was purified by chromatography on silica gel eluting with 8% ethyl acetate/hexanes, and the fractions were collected and concentrated to give 5-bromo-3- (2, 2-difluoroethyl) -1H-indole (120mg, 0.438mmol) as an oil. LC retention time 2.802 min. [ D ] ]。MS(E-)m/z：260(M+H)。
Intermediate 161E: 4- (3- (2, 2-difluoroethyl) -1H-indol-5-yl) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester
Figure BDA0001979596660001921
4- (3- (2, 2-difluoroethyl) -1H-indol-5-yl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester was prepared according to the general procedure described for intermediate T-1B using 5-bromo-3- (2, 2-difluoroethyl) -1H-indole as the starting intermediate (0.14g, 80% yield). LC retention time 3.075 min. [ D ]]。MS(E-)m/z：361.2(M-H)。
Intermediate 161F: 4- (3- (2, 2-difluoroethyl) -1H-indol-5-yl) piperidine-1-carboxylic acid tert-butyl ester
Figure BDA0001979596660001922
4- (3- (2, 2-difluoroethyl) -1H-indol-5-yl) piperidine-1-carboxylic acid tert-butyl ester radicalPrepared according to the general procedure described for intermediate T-1C using tert-butyl 4- (3- (2, 2-difluoroethyl) -1H-indol-5-yl) -5, 6-dihydropyridine-1 (2H) -carboxylate as starting intermediate (0.9g, 88% yield). LC retention time 3.282 min. [ D ]]。MS(E-)m/z：265.0(M+H-Boc)。
Intermediate 161G: 4- (2-bromo-3- (2, 2-difluoroethyl) -1H-indol-5-yl) piperidine-1-carboxylic acid tert-butyl ester
Figure BDA0001979596660001923
Tert-butyl 4- (2-bromo-3- (2, 2-difluoroethyl) -1H-indol-5-yl) piperidine-1-carboxylate was prepared according to the general procedure described for intermediate 194D using tert-butyl 4- (3- (2, 2-difluoroethyl) -1H-indol-5-yl) piperidine-1-carboxylate as the starting intermediate (0.3g, 52% yield). LC retention time 1.10 min. [ G ] ]。MS(E-)m/z：389.0(M+2H-tBu)。
Intermediate 161H: 4- (3- (2, 2-Difluoroethyl) -2- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-indol-5-yl) piperidine-1-carboxylic acid tert-butyl ester
Figure BDA0001979596660001931
A mixture of pinacol diboron (1.444g, 11.28mmol), tert-butyl 4- (2-bromo-3- (2, 2-difluoroethyl) -1H-indol-5-yl) piperidine-1-carboxylate (1.0g, 2.256mmol), bis (benzonitrile) palladium (II) chloride (0.086g, 0.226mmol), TEA (0.683g, 6.77mmol) and 2-dicyclohexylphosphino-2 ', 6' -dimethoxybiphenyl (0.092g, 0.226mmol) in dioxane (20mL) was degassed with nitrogen for 10 min. The reaction mixture was stirred at 80 ℃ for 1h in a sealed tube. The reaction was quenched with ice-cold water. The reaction mixture was diluted with ethyl acetate, filtered and washed with excess ethyl acetate, and the combined organic layers were washed with water, brine, dried over sodium sulfate and evaporated to give crude compound. The crude material was purified by silica gel chromatography, the compound was eluted with 25% ethyl acetate in hexane, fractions were collected and concentrated to give an off-white solidTert-butyl 4- (3- (2, 2-difluoroethyl) -2- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-indol-5-yl) piperidine-1-carboxylate (0.650g, 1.325mmol, 58.8% yield). LC retention time 3.282 min. [ D ] ]。MS(E-)m/z：435.4(M+H-tBu)。
Intermediate 161I: 4- (3- (2, 2-difluoroethyl) -2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidine-1-carboxylic acid tert-butyl ester
Figure BDA0001979596660001932
4- (3- (2, 2-Difluoroethyl) -2- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-indol-5-yl) piperidine-1-carboxylic acid tert-butyl ester (0.300, 0.612mmol), 6-bromo-8-methyl- [1, 2, 4-difluoromethyl ] -2- (4, 4, 5, 5-tetramethyl-1, 2-dioxaborolan-2-yl)]Triazolo [1, 5-a]Pyridine (0.156g, 0.734mmol), PdCl2(dppf)-CH2Cl2A mixture of the adduct (0.050g, 0.061mmol) and potassium phosphate (0.390g, 1.835mmol) in a solvent mixture of dioxane (20mL) and water (2.5mL) was degassed with nitrogen for 10 min. The resulting slurry was then stirred in a sealed tube at 95 ℃ for 3 h. The reaction mixture was diluted with ethyl acetate, filtered and washed with excess ethyl acetate, and the combined organic layers were washed with water, brine, dried over sodium sulfate and evaporated to give crude compound. The crude material was purified by silica gel chromatography eluting with 85% ethyl acetate and petroleum ether to give 4- (3- (2, 2-difluoroethyl) -2- (8-methyl- [1, 2, 4] as a pale yellow solid]Triazolo [1, 5-a]Pyridin-6-yl) -1H-indol-5-yl) piperidine-1-carboxylic acid tert-butyl ester (0.210g, 0.424mmol, 69.3% yield). LC retention time 1.42 min. [ G ] ]。MS(E-)m/z：496.4(M+H)。
Example 161:
to 4- (3- (2, 2-difluoroethyl) -2- (8-methyl- [1, 2, 4] methyl ester at room temperature]Triazolo [1, 5-a]To a solution of pyridin-6-yl) -1H-indol-5-yl) piperidine-1-carboxylic acid tert-butyl ester (0.210g, 0.424mmol) in dioxane (5.0mL) was added 4M HCl in dioxane (1.059mL, 4.24 mmol). The mixture was stirred at the same temperature for 2 h. Evaporating the volatiles and vacuum drying to obtain a crude mixtureA compound (I) is provided. The crude material was triturated with ether and dried in vacuo to give 6- (3- (2, 2-difluoroethyl) -5- (piperidin-4-yl) -1H-indol-2-yl) -8-methyl- [1, 2, 4] as a pale yellow solid]Triazolo [1, 5-a]Pyridine (0.165g, 0.417mmol, 98% yield). LCMS retention time 1.021 min. [ E ]]。MS(E-)m/z：396.2(M+H)。
Example 162
6- (3- (2, 2-difluoroethyl) -5- (piperidin-4-yl) -1H-indol-2-yl) -2, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridine
Figure BDA0001979596660001941
Intermediate 162A: 4- (3- (2, 2-Difluoroethyl) -2- (2, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidine-1-carboxylic acid tert-butyl ester
Figure BDA0001979596660001942
4- (3- (2, 2-difluoroethyl) -2- (2, 8-dimethyl- [1, 2, 4)]Triazolo [1, 5-a]Pyridin-6-yl) -1H-indol-5-yl) piperidine-1-carboxylic acid tert-butyl ester was prepared according to the general procedure described for intermediate 161I using tert-butyl 4- (3- (2, 2-difluoroethyl) -2- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-indol-5-yl) piperidine-1-carboxylate (0.250g, 0.510 mmol). LC retention time 3.102 min. [ D ] ]。MS(E-)m/z：510.2(M+H)。
Example 162:
6- (3- (2, 2-difluoroethyl) -5- (piperidin-4-yl) -1H-indol-2-yl) -2, 8-dimethyl- [1, 2, 4]Triazolo [1, 5-a]Pyridine the general procedure described in example 161 was followed using 4- (3- (2, 2-difluoroethyl) -2- (2, 8-dimethyl- [1, 2, 4]]Triazolo [1, 5-a]Pyridin-6-yl) -1H-indol-5-yl) piperidine-1-carboxylic acid tert-butyl ester (0.200g, 0.392 mmol). LC retention time 1.831 min. [ D ]]。MS(E-)m/z：410.2(M+H)。
The following examples were prepared according to the general procedure disclosed in example 7.
TABLE 11
Figure BDA0001979596660001951
Figure BDA0001979596660001961
Figure BDA0001979596660001971
Figure BDA0001979596660001981
Figure BDA0001979596660001991
Figure BDA0001979596660002001
Figure BDA0001979596660002011
Figure BDA0001979596660002021
Figure BDA0001979596660002031
TABLE 12
Figure BDA0001979596660002032
Figure BDA0001979596660002041
Figure BDA0001979596660002051
Figure BDA0001979596660002061
Figure BDA0001979596660002071
Figure BDA0001979596660002081
Figure BDA0001979596660002091
Figure BDA0001979596660002101
Figure BDA0001979596660002111
Figure BDA0001979596660002121
Figure BDA0001979596660002131
Figure BDA0001979596660002141
Figure BDA0001979596660002151
Figure BDA0001979596660002161
The following examples were prepared according to the general procedure of example 26.
Watch 13
Figure BDA0001979596660002162
Figure BDA0001979596660002171
Figure BDA0001979596660002181
Figure BDA0001979596660002191
Figure BDA0001979596660002201
Figure BDA0001979596660002211
Figure BDA0001979596660002221
Figure BDA0001979596660002231
Figure BDA0001979596660002241
Figure BDA0001979596660002251
Figure BDA0001979596660002261
Figure BDA0001979596660002271
Figure BDA0001979596660002281
Figure BDA0001979596660002291
Figure BDA0001979596660002301
Figure BDA0001979596660002311
Figure BDA0001979596660002321
Figure BDA0001979596660002331
Figure BDA0001979596660002341
Figure BDA0001979596660002351
Figure BDA0001979596660002361
Figure BDA0001979596660002371
TABLE 14
Figure BDA0001979596660002372
Figure BDA0001979596660002381
Figure BDA0001979596660002391
Figure BDA0001979596660002401
Figure BDA0001979596660002411
Figure BDA0001979596660002421
Figure BDA0001979596660002431
Figure BDA0001979596660002441
Figure BDA0001979596660002451
Figure BDA0001979596660002461
The following examples were prepared according to the general methods disclosed in examples 46 and 47.
Watch 15
Figure BDA0001979596660002462
Figure BDA0001979596660002471
TABLE 16
Figure BDA0001979596660002472
Figure BDA0001979596660002481
Figure BDA0001979596660002491
Figure BDA0001979596660002501
Figure BDA0001979596660002511
Figure BDA0001979596660002521
Figure BDA0001979596660002531
Figure BDA0001979596660002541
Figure BDA0001979596660002551
Figure BDA0001979596660002561
Figure BDA0001979596660002571
Figure BDA0001979596660002581
Figure BDA0001979596660002591
Figure BDA0001979596660002601
The following examples were prepared in accordance with the general procedure disclosed in example 68.
TABLE 17
Figure BDA0001979596660002602
Figure BDA0001979596660002611
Figure BDA0001979596660002621
Figure BDA0001979596660002631
Figure BDA0001979596660002641
Figure BDA0001979596660002651
Figure BDA0001979596660002661
Figure BDA0001979596660002671
Figure BDA0001979596660002681
Watch 18
Figure BDA0001979596660002682
Figure BDA0001979596660002691
Figure BDA0001979596660002701
The following examples were prepared according to the general procedure described in example 74.
Watch 19
Figure BDA0001979596660002702
Figure BDA0001979596660002711
Figure BDA0001979596660002721
Figure BDA0001979596660002731
Figure BDA0001979596660002741
Figure BDA0001979596660002751
Figure BDA0001979596660002761
Figure BDA0001979596660002771
Figure BDA0001979596660002781
Watch 20
Figure BDA0001979596660002782
Figure BDA0001979596660002791
Figure BDA0001979596660002801
Figure BDA0001979596660002811
Example 882
1- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -3-morpholinopropan-1-one
Figure BDA0001979596660002821
To a 2 dram vial was added 6- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) -7-methyl- [1, 2, 4]Triazolo [1, 5-a]Pyridine TFA salt (0.025g, 0.053mmol), CH 3CN, HATU (1.0 equiv.), TEA (3.0 equiv.), and 3-morpholinopropionic acid (0.250g, 1.570 mmol). The reaction vial was capped and stirred at room temperature overnight. Solvent for the mixture (90: 10: 0.1 CH)3CN: water: TFA) and filtered. The crude material was purified via preparative LC/MS using the following conditions: column: XBridge C18, 19 × 200mm, 5 μm particles; mobile phase A: 5: 95 acetonitrile: water +10mM ammonium acetate; mobile phase B: 95: 5 acetonitrile: water +10mM ammonium acetate; gradient: 10-70% B over 19 minutes, followed by 3 minutes at 100% B; flow rate: 20 mL/min. The fractions containing the desired product were combined and dried by centrifugal evaporation to give 1- (4- (3-isopropyl-2- (8-methyl- [1, 2, 4)]Triazolo [1, 5-a]Pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -3-morpholinopropan-1-one (21.2mg, 0.041mmol, 78% yield). LCMS MH+: 515.2. HPLC retention time 1.52 min. Method QC-ACN-AA-XB.1H NMR(500MHz，DMSO-d6)δ8.85-8.72(m，1H)，8.55-8.48(m，1H)，7.63-7.50(m，2H)，7.36-7.22(m，1H)，7.06-6.94(m，1H)，4.63-4.51(m，1H)，4.06-3.98(m，1H)，3.63-3.56(m，5H)，3.30-3.20(m，1H)，2.70-2.53(m，11H)，2.46-2.39(m，3H)，1.89-1.79(m，2H)，1.70-1.59(m，1H)，1.53-1.46(m，1H)，1.45-1.39(m，6H)。
The following examples are prepared in accordance with the general procedures described in example 882.
TABLE 21
Figure BDA0001979596660002822
Figure BDA0001979596660002831
Figure BDA0001979596660002841
Figure BDA0001979596660002851
Figure BDA0001979596660002861
Figure BDA0001979596660002871
Figure BDA0001979596660002881
Example 927
4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidine-1-carboxylic acid azetidin-3-yl ester
Figure BDA0001979596660002882
Mixing 4- (2- (7, 8-dimethyl- [1, 2, 4]]Triazolo [1, 5-a ]Pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidine-1-carboxylic acid 1- (tert-butoxycarbonyl) azetidin-3-yl ester (15mg, 0.026mmol) and 2: 1 trifluoroacetic acid: dichloromethane (1.2mL, 0.026mmol) were combined in a 1 dram vial with a stir bar. The resulting clear yellow solution was stirred at room temperature for 30 min. After completion of the reaction, toluene (150. mu.L) was added to the reaction mixture. The reaction mixture was stirred briefly and the excess solvent was evaporated. The residue was taken up in DMF (1.5mL) and purified by semi-preparative HPLC on a C-18 column on a Shimadzu instrument eluting with water/acetonitrile/TFA. The excess solvent was evaporated from the product-containing fractions to give 4- (2- (7, 8-dimethyl- [1, 2, 4) as a white solid]Triazolo [1, 5-a]Pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidine-1-carboxylic acid azetidin-3-yl ester TFA (14.9mg, 0.025mmol, 96% yield). LCMS MH+: 487.3. HPLC retention time 1.40 min. Method QC-ACN-TFA-XB.1H NMR (400MHz, methanol-d)4)δ8.68(s，1H)，8.58(s，1H)，7.60(s，1H)，7.33(d，J＝8.3Hz，1H)，7.08(dd，J＝8.4，1.5Hz，1H)，5.33-5.24(m，1H)，4.45(dd，J＝12.7，7.0Hz，2H)，4.38-4.25(m，2H)，4.21(br.s.，2H)，3.17-3.06(m，1H)，2.98(dq，J＝13.6，6.8Hz，4H)，2.88(tt，J＝12.0，3.3Hz，1H)，2.67(s，3H)，2.30(s，3H)，1.96(d，J＝12.0Hz，2H)，1.75(br.s.，2H)，1.40(d，J＝7.1Hz，6H)。
The following examples are prepared in accordance with the general procedure set forth in example 929.
TABLE 22
Figure BDA0001979596660002891
Figure BDA0001979596660002901
Figure BDA0001979596660002911
Figure BDA0001979596660002921
Figure BDA0001979596660002931
Example 957
(4- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) (4-methylpiperazin-1-yl) methanone
Figure BDA0001979596660002932
Mixing 6- (3-isopropyl-5- (piperidine-4-yl) -1H-indol-2-yl) -7, 8-dimethyl- [1, 2, 4]Triazolo [1, 5-a]Pyridine (10mg, 0.026mmol) was dissolved in THF (0.25 mL). Phenyl chloroformate (6.06mg, 0.039mmol) was added to the solution. The reaction mixture was stirred at room temperature overnight. The reaction mixture was washed on a ZYmark Turbovap for 1h at 45 ℃. The residue was dissolved in NMP (0.25 mL). To the intermediate in NMP was then added 1-methylpiperazine (7.75mg, 0.077mmol) and DIPEA (6.76. mu.l, 0.039 mmol). The reaction mixture was stirred at 100 ℃ overnight. The crude sample in a short crude tube (final volume 1.8mL in DMF/NMP) was purified via preparative LC/MS using the following conditions: column: XBridge C18, 19 × 200mm, 5 μm particles; mobile phase A: 5: 95 acetonitrile: water +10mM ammonium acetate; mobile phase B: 95: 5 acetonitrile: water +10mM ammonium acetate; gradient: 20-60% B over 20 minutes, followed by 5 minutes at 100% B; flow rate: 20 mL/min. The product-containing fractions were combined and dried by centrifugal evaporation to give (4- (2- (7, 8-dimethyl- [1, 2, 4)]Triazolo [1, 5-a]Pyridine compound-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) (4-methylpiperazin-1-yl) methanone (4mg, 7.63 μmol, 29.6% yield). LCMS MH +: 514.4. HPLC retention time 1.29 min. Method QC-ACN-TFA-XB.
The following examples were prepared in accordance with the general procedure described in example 957.
TABLE 23
Figure BDA0001979596660002941
Figure BDA0001979596660002951
Figure BDA0001979596660002961
Figure BDA0001979596660002971
Example 981
2- (3- (2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) -8-azabicyclo [3.2.1] oct-8-yl) acetonitrile
Figure BDA0001979596660002972
Intermediate 981A: 3-isopropyl-1H-indoles
Figure BDA0001979596660002973
To a 500mL round bottom flask were added 2, 2, 2-trichloroacetic acid (23.60g, 144mmol), toluene (150mL), and triethylsilane (46.1mL, 289 mmol). The solution was heated to 70 ℃ with stirring and 1H-indole (11.28g, 96mmol) and acetone (8.48mL, 116mmol) were added dropwise to 75mL via addition funnelSolution in toluene. The reaction mixture was heated to 90 ℃ and held for 2.5 hours. The reaction mixture was cooled to room temperature and subsequently to 5 ℃. To this was added 1.5M dipotassium hydrogenphosphate solution and diethyl ether. The layers were separated and the organic layer was washed with brine, over Na2SO4Dried, filtered and concentrated. The residue was purified on silica gel using ethyl acetate/hexanes as the eluent to give 3-isopropyl-1H-indole (12g, 78%) as a white solid. LC retention time 1.04 min. [ A1]。MS(E+)m/z：160.2(M+H)。1H NMR (400MHz, chloroform-d) δ 7.72-7.65(m, 1H), 7.41-7.36(m, 1H), 7.21(d, J ═ 0.9Hz, 1H), 7.14(s, 1H), 6.99(dd, J ═ 2.2, 0.7Hz, 1H), 3.31-3.17(m, 1H), 1.40(d, J ═ 6.8Hz, 6H).
Intermediate 981B: 6- (3-isopropyl-1H-indol-2-yl) -7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridine
Figure BDA0001979596660002981
To a 100mL round bottom flask was added 3-isopropyl-1H-indole (1.000g, 6.28mmol) and DCE (10 mL). NBS (1.062g, 5.97mmol) was dissolved in 10mL DCE and added dropwise to the reaction mixture over 15 minutes via an addition funnel. The reaction was quenched with 5mL of 10% sodium sulfite solution. The volatiles were removed. THF (10mL), 7, 8-dimethyl-6- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) - [1, 2, 4] was then added]Triazolo [1, 5-a]Pyridine (1.54g, 5.56mmol), PdCl2(dppf)-CH2Cl2Adduct (0.25g, 0.314. mu. mol) and 3M potassium phosphate solution (6.3mL, 18.8 mmol). The reaction vessel was capped and pumped/flushed with nitrogen three times. The reaction mixture was set to heat at 70 ℃ for 1 hour. The mixture was cooled to room temperature and concentrated. The crude residue was taken up in DCM (3mL), filtered and purified on silica gel using ethyl acetate/hexane to give 6- (3-isopropyl-1H-indol-2-yl) -7, 8-dimethyl- [1, 2, 4-dimethyl ] as a white foam]Triazolo [1, 5-a]Pyridine (0.8g, 41.8%). LC retention time 2.04 min. [ D1]。MS(E+)m/z：305.0(M+H)。1H NMR (400MHz, methanol)-d4)δ8.54-8.44(m，1H)，8.38-8.28(m，1H)，7.56(d，J＝1.1Hz，1H)，7.45(d，J＝8.4Hz，1H)，7.13-7.01(m，2H)，3.28-3.16(m，1H)，2.66(s，3H)，2.32(s，3H)，1.38(d，J＝6.8Hz，6H)。
Intermediate 981C: 5-bromo-2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indole-1-carboxylic acid tert-butyl ester
Figure BDA0001979596660002982
To a 40mL reaction vial was added 6- (3-isopropyl-1H-indol-2-yl) -7, 8-dimethyl- [1, 2, 4]Triazolo [1, 5-a]Pyridine (0.450g, 1.478mmol), AcOH (4mL), water (0.5mL) and NBS (0.263g, 1.478 mmol). The vial was sealed and stirred at 80 ℃ for 30 minutes. The reaction mixture was cooled to room temperature and 1mL of 10% sodium sulfite was added. The mixture was concentrated, dissolved in DCM/MeOH, filtered and purified on silica gel using ethyl acetate/hexane to give 5-bromo-2- (7, 8-dimethyl- [1, 2, 4 ] as a brown solid]Triazolo [1, 5-a]Pyridin-6-yl) -3-isopropyl-1H-indole. LC retention time 1.01 min. [ A1]。MS(E+)m/z：83/385(M+H)。1H NMR(400MHz，DMSO-d6)δ11.26(s，1H)，8.82(s，1H)，8.48(s，1H)，7.70(d，J＝8.4Hz，1H)，7.52(d，J＝1.5Hz，1H)，7.16(dd，J＝8.6，1.8Hz，1H)，2.88(br d，J＝14.1Hz，1H)，2.60(s，3H)，2.15(s，3H)，1.43-1.15(m，5H)，1.18-1.09(m，1H)。
To this material were added DMAP (0.010g, 0.0148mmol), THF (10mL) and BOC anhydride (0.59g, 2.95 mmol). The reaction mixture was stirred at rt for 2 h, concentrated to a viscous oil, diluted with DCM and washed with dilute 1N HCl. The organics were washed with water followed by brine. The solution is passed through Na2SO4Dried, filtered and concentrated. The residue was purified on silica gel using ethyl acetate/hexane to give 5-bromo-2- (7, 8-dimethyl- [1, 2, 4 ] dimethyl- [1, 7, 8 ] as a yellow solid]Triazolo [1, 5-a]Pyridin-6-yl) -3-isopropyl-1H-indole-1-carboxylic acid tert-butyl ester (0.45g, 63%). LC retention time 1.15 min. [ A1 ]。MS(E+)m/z：483/485(M+H)。
Intermediate 981D: 5- (8- (tert-Butoxycarbonyl) -8-azabicyclo [3.2.1] oct-2-en-3-yl) -2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indole-1-carboxylic acid tert-butyl ester
Figure BDA0001979596660002991
In a screw cap vial to 5-bromo-2- (7, 8-dimethyl- [1, 2, 4]]Triazolo [1, 5-a]Pyridin-6-yl) -3-isopropyl-1H-indole-1-carboxylic acid tert-butyl ester (0.130g, 0.269mmol), PdCl2(dppf)-CH2Cl2Adduct (10.98mg, 0.013mmol) and (8- (tert-butoxycarbonyl) -8-azabicyclo [ 3.2.1)]To a mixture of oct-3-en-3-yl) boronic acid (0.071g, 0.282mmol) was added THF (2mL) followed by 3M aqueous potassium phosphate (0.269mL, 0.807 mmol). The vial was equipped with a teflon-lined septum cap. The system was evacuated under vacuum and backfilled with nitrogen. This procedure was repeated three times. The vial was sealed and heated at 75 ℃ for 18 hours. The reaction mixture was diluted with EtOAc (100mL) and poured into a separatory funnel. The organic layer was washed with water (2X 50mL), saturated aqueous NaCl solution (50mL) and dried (Na)2SO4) Filtered and concentrated in vacuo to give the crude product. The crude product was purified on silica gel using 0-100% ethyl acetate/hexane. After concentration of the fractions, the product was collected as a brown oil (0.11g, 65%). LC retention time 1.19 min. [ A1 ]。MS(E+)m/z：612.2(M+H)。
Intermediate 981E: 5- (8- (tert-Butoxycarbonyl) -8-azabicyclo [3.2.1] oct-3-yl) -2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indole-1-carboxylic acid tert-butyl ester
Figure BDA0001979596660003001
In a Pal bottle 5- (8- (tert-butoxycarbonyl) -8-azabicyclo [3.2.1]]Oct-2-en-3-yl) -2- (7, 8-dimethyl- [1, 2, 4]Triazolo [1, 5-a]Pyridin-6-yl) -3-isopropyl-1H-indole-1-carboxylic acid tert-butyl ester (0)11g, 0.18mmol) was suspended in ethyl acetate (3mL) and treated with 10 mol% 5% Pd/C (0.057g, 0.027 mmol). After degassing, the reaction mixture was placed under an atmosphere of hydrogen (50psi) and shaken at room temperature for 16 hours. After removal of the hydrogen atmosphere and backfilling with nitrogen, the reaction mixture was diluted with MeOH, filtered through celite and concentrated to give 5- (8- (tert-butoxycarbonyl) -8-azabicyclo [3.2.1] as an isomeric mixture]Oct-3-yl) -2- (7, 8-dimethyl- [1, 2, 4]Triazolo [1, 5-a]Pyridin-6-yl) -3-isopropyl-1H-indole-1-carboxylic acid tert-butyl ester (0.11g, 100%). LC retention time 1.20 min. [ A1]。MS(E+)m/z：614.4(M+H)。
Intermediate 981F: 6- (5- (8-azabicyclo [3.2.1] oct-3-yl) -3-isopropyl-1H-indol-2-yl) -7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridine TFA salt
Figure BDA0001979596660003002
To a solution of tert-butyl 5- (8- (tert-butoxycarbonyl) -8-azabicyclo [3.2.1] oct-3-yl) -2- (7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indole-1-carboxylate (0.025g, 0.041mmol) in a 2-dram reaction vial was added DCM (0.5 mL). TFA (1mL) was added thereto and the reaction vial was capped. The reaction mixture was stirred at room temperature for 2 hours. Volatiles were removed under a stream of nitrogen. The yield was considered quantitative. This material was used as such for final derivatization to prepare the compounds shown in table 24. An example is described below with respect to example 981.
Example 981:
to a 2-dram reaction vial was added 6- (5- (8-azabicyclo [3.2.1]]Oct-3-yl) -3-isopropyl-1H-indol-2-yl) -7, 8-dimethyl- [1, 2, 4]Triazolo [1, 5-a]Pyridine TFA salt (0.021g, 0.041mmol), NMP, DBU (0.025mL, 0.164mmol) and bromoacetonitrile (0.017g, 0.15mmol) were added dropwise. The reaction mixture was stirred at room temperature for 1 hour, then diluted with water and filtered through a 0.45 micron syringe filter. The crude material was purified via preparative LC/MS using the following conditions: column: XBridge C18, 19 × 200mm, 5 μm particles; mobile phase A: 595 acetonitrile, water and 10mM ammonium acetate; mobile phase B: 95: 5 acetonitrile: water +10mM ammonium acetate; gradient: 40-80% B over 25 minutes, followed by 5 minutes at 100% B; flow rate: 20 mL/min. The fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparative LC/MS using the following conditions: column: XBridge C18, 19 × 200mm, 5 μm particles; mobile phase A: 5: 95 acetonitrile: water +10mM ammonium acetate; mobile phase B: 95: 5 acetonitrile: water +10mM ammonium acetate; gradient: 35-75% B over 20 minutes, followed by 5 minutes at 100% B; flow rate: 20 mL/min. The fractions containing the desired product were combined and dried via centrifugal evaporation. Collecting 2- (3- (2- (7, 8-dimethyl- [1, 2, 4) in the form of an isomeric mixture ]Triazolo [1, 5-a]Pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) -8-azabicyclo [3.2.1]Oct-8-yl) acetonitrile (0.0021g, 6.4% yield). Two analytical LC/MS injections were used to determine the final purity. LC retention time 2.18 min. [ C1]。MS(E+)m/z：453.0(M+H)。1H NMR(500MHz，DMSO-d6)δ10.95(br d，J＝18.2Hz，1H)，8.73-8.64(m，1H)，8.69(br s，1H)，8.52-8.39(m，1H)，8.46(s，1H)，7.62(s，1H)，7.62(br d，J＝18.2Hz，1H)，7.19(s，1H)，7.23(br s，1H)，7.01-6.88(m，1H)，7.05-6.84(m，1H)，3.34(br s，1H)，3.17(s，1H)，3.13-3.01(m，1H)，2.99-2.93(m，1H)，2.88-2.76(m，1H)，2.57(s，2H)，2.15(s，2H)，2.02-1.94(m，1H)，1.90(br d，J＝8.2Hz，1H)，1.75(br s，4H)，1.68-1.57(m，1H)，1.29(br s，5H)。
The following examples were prepared according to the general procedure disclosed in example 981.
Watch 24
Figure BDA0001979596660003011
Figure BDA0001979596660003021
Example 986
6- (3-isopropyl-5- (1- (pyridin-2-yl) piperidin-4-yl) -1H-indol-2-yl) -7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridine
Figure BDA0001979596660003022
Mixing 6- (3-isopropyl-5- (piperidine-4-yl) -1H-indol-2-yl) -7, 8-dimethyl- [1, 2, 4]Triazolo [1, 5-a]Pyridine (19.4mg, 0.050mmol), 2-chloropyridine (6.2mg, 0.055mmol), 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (5.8mg, 10.00. mu. mol), Pd2(dba)3(4.6mg, 5.00. mu. mol) and Cs2CO3(48.9mg, 0.150mmol) was suspended in dioxane (0.5 mL). The mixture was degassed with nitrogen for 5 minutes. The reaction vessel was sealed and heated to 90 ℃ and held for 2 hours. Upon completion, the reaction mixture was filtered, concentrated, dissolved in DMF and purified via preparative LCMS using the following conditions: column: XBridge C18, 19 × 200mm, 5 μm particles; mobile phase A: 5: 95 acetonitrile: water + 0.1% trifluoroacetic acid; mobile phase B: 95: 5 acetonitrile: water + 0.1% trifluoroacetic acid; gradient: 10-50% B over 19 minutes, followed by 5 minutes at 100% B; flow rate: 20 mL/min. The product containing fractions were combined and dried by centrifugal evaporation to give 6- (3-isopropyl-5- (1- (pyridin-2-yl) piperidin-4-yl) -1H-indol-2-yl) -7, 8-dimethyl- [1, 2, 4 ]Triazolo [1, 5-a]Pyridine TFA (10.1mg, 0.017mmol, 35% yield). LCMS Retention time 1.25[ QC-ACN-TFA-XB]。MS(ES+)m/z：465.4(M+H)。1H NMR(500MHz，DMSO-d6)δ8.81(s，1H)，8.63(br d，J＝7.9Hz，1H)，8.44-8.38(m，2H)，8.36(br d，J＝9.5Hz，1H)，7.82-7.73(m，1H)，7.67(s，1H)，7.48(d，J＝8.5Hz，1H)，7.28-7.24(m，1H)，7.22(d，J＝7.9Hz，1H)，7.12(br d，J＝8.5Hz，1H)，3.41(br d，J＝11.3Hz，2H)，3.11-2.93(m，3H)，2.85(dt，J＝14.0，7.0Hz，1H)，2.42(s，3H)，2.06-1.96(m，2H)，1.96-1.82(m，5H)，1.35(dd，J＝16.5，7.0Hz，6H)。
The following examples were prepared in a similar manner to example 986.
TABLE 25
Figure BDA0001979596660003023
Figure BDA0001979596660003031
Example 989
6- (3-isopropyl-5- (1- (pyrimidin-2-yl) piperidin-4-yl) -1H-indol-2-yl) -7, 8-dimethyl- [1, 2, 4] triazolo [1, 5-a ] pyridine
Figure BDA0001979596660003032
Mixing 6- (3-isopropyl-5- (piperidine-4-yl) -1H-indol-2-yl) -7, 8-dimethyl- [1, 2, 4]Triazolo [1, 5-a]Pyridine (19.4mg, 0.050mmol) and Et3N (0.021mL, 0.150mmol) was mixed in DMSO (1 mL). 2-Chloropyrimidine (6.9mg, 0.060mmol) was then added. The reaction vial was sealed and heated to 90 ℃ and held for 2 hours. Upon completion, the reaction mixture was cooled to room temperature, diluted with water (0.05mL) and 1mL DMSO and purified on preparative LCMS via the following conditions: column: XBridge C18, 19 × 200mm, 5 μm particles; mobile phase A: 5: 95 acetonitrile: water +10mM ammonium acetate; mobile phase B: 95: 5 acetonitrile: water +10mM ammonium acetate; gradient: 45-100% B over 20 minutes, followed by 10 minutes at 100% B; flow rate: 20 mL/min. The product containing fractions were combined and dried by centrifugal evaporation to give 6- (3-isopropyl-5- (1- (pyrimidin-2-yl) piperidin-4-yl) -1H-indol-2-yl) -7, 8-dimethyl- [1, 2, 4 ]Triazolo [1, 5-a]Pyridine (5.0mg, 10.2. mu. mol, 20.4% yield). LCMS Retention time 1.71[ QC-ACN-TFA-XB]。MS(ES+)m/z：466.3(M+H)。
Example 990
2- (4- (2- (8-amino- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -N, N-dimethylacetamide
Figure BDA0001979596660003041
To 2- (4- (2- (8- (benzylamino) - [1, 2, 4) ]]Triazolo [1, 5-a]Pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -N, N-dimethylacetamide (0.040g, 0.073mmol) was added to a solution of Pd/C (0.023g, 0.218mmol) in methanol (10.0 mL). The reaction mixture was stirred at room temperature under hydrogen for 6 h. The reaction mixture was diluted with ethyl acetate: methanol (1: 1), filtered and washed with excess ethyl acetate. The combined organic layers were evaporated to give crude compound. The crude material was purified via preparative LC/MS using the following conditions: column: waters XBridge C18, 19 × 150mm, 5 μm particles; mobile phase A: 0.05% TFA; mobile phase B: acetonitrile; gradient: 15-50% B over 20 minutes, followed by 5 minutes at 100% B; flow rate: 15 mL/min. The product-containing fractions were combined and dried by centrifugal evaporation to give 2- (4- (2- (8-amino- [1, 2, 4)]Triazolo [1, 5-a]Pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -N, N-dimethylacetamide (7.3 mg). LCMS retention time 1.44 min. [ E ] ]。MS(E-)m/z：460.3(M-H)。1H NMR (400MHz, methanol-d)4)δppm 8.31-8.39(m，1H)8.16(d，J＝1.47Hz，1H)7.66(s，1H)7.36(d，J＝8.31Hz，1H)7.08(d，J＝8.80Hz，1H)6.84-6.97(m，1H)4.26(s，2H)3.76(d，J＝13.21Hz，2H)3.33-3.43(m，2H)3.25(br.s.，2H)2.94-3.12(m，8H)2.19(br.s.，4H)1.50(d，J＝7.09Hz，7H)1.28(br.s.，1H)。
Example 991
2- (4- (4-fluoro-3-isopropyl-2- (8-methoxy- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -N, N-dimethylacetamide
Figure BDA0001979596660003042
Intermediate 991A: 4-fluoro-3-isopropyl-1H-indoles
Figure BDA0001979596660003043
To a lid with red pressure reliefA40 mL vial was charged with 2, 2, 2-trichloroacetic acid (0.907g, 5.55mmol), toluene (7.40mL), and triethylsilane (1.773mL, 11.10 mmol). The solution was heated to 70 ℃ with stirring and a solution of 4-fluoro-1H-indole (0.500g, 3.70mmol) and acetone (0.326mL, 4.44mmol) in 1mL of toluene was added dropwise via syringe. The reaction mixture was stirred and heated to 90 ℃ and held for 3h, purged with nitrogen line. The reaction mixture was cooled to 5 ℃ and 1M K was added to the reaction mixture3PO4Aqueous solution (about 4mL) and ethyl acetate (4 mL). The layers were separated and the aqueous phase was extracted with EtOAc (2X 5 mL). The combined organic extracts were dried over sodium sulfate and filtered and the excess solvent was evaporated off. The resulting red oil was taken up in DCM (ca 2mL) and purified by flash chromatography to give 4-fluoro-3-isopropyl-1H-indole (483.2mg, 2.67mmol, 72.2% yield) as a yellow liquid.1H NMR (400MHz, chloroform-d) δ 7.97(br s, 1H), 7.16-7.07(m, 2H), 6.95(d, J ═ 2.2Hz, 1H), 6.77(ddd, J ═ 11.3, 7.4, 1.1Hz, 1H), 3.38(dt, J ═ 13.7, 6.8Hz, 1H), 1.38(dd, J ═ 6.8, 0.6Hz, 6H). HPLC retention time 0.99 min. Method G.
Intermediate 991B: 4-fluoro-3-isopropyl-1- (triisopropylsilyl) -1H-indole
Figure BDA0001979596660003051
4-fluoro-3-isopropyl-1H-indole (0.475g, 2.68mmol) was dissolved in THF (10.72mL) in a 40mL vial. The solution was cooled to 0 ℃ with an ice bath under a nitrogen atmosphere and sodium hydride (0.214g, 5.36mmol) was added to the reaction mixture. The reaction mixture was warmed to room temperature, followed by dropwise addition of triisopropylsilyl chloride (0.860mL, 4.02mmol) via syringe. The reaction mixture was then stirred at 50 ℃ for 1 h. The reaction was complete. The reaction mixture was cooled to 0 ℃ and purified by addition of 1M KHSO4(about 4mL) and water (4 mL). Ethyl acetate (4mL) was added and the phases separated. The aqueous phase was extracted with ethyl acetate (2X 3 mL). The combined organic phases were extracted with brine (1X 4mL) and the excess solvent was evaporated off. The resulting yellow oil was taken up in DCM (total volume about 3.5mL) and flash chromatographed on 24g of siliconPurifying with gel column eluting with ethyl acetate and hexane. The product, 4-fluoro-3-isopropyl-1- (triisopropylsilyl) -1H-indole (0.92g, 2.48mmol, 92% yield), was obtained as a clear colorless liquid.1H NMR (400MHz, chloroform-d) δ 7.24(d, J ═ 8.3Hz, 1H), 7.03(td, J ═ 8.1, 5.4Hz, 1H), 6.94(s, 1H), 6.76(dd, J ═ 11.0, 7.8Hz, 1H), 3.36(spt, J ═ 6.8Hz, 1H), 1.36(d, J ═ 6.8Hz, 6H), 1.16(d, J ═ 7.6Hz, 18H). LCMS MH +: 334.3. HPLC retention time 1.43 min. Method G.
Intermediate 991C: 5-bromo-4-fluoro-3-isopropyl-1- (triisopropylsilyl) -1H-indole
Figure BDA0001979596660003061
Sec-butyllithium (2.144mL, 3.00mmol, 90% purity) was added to a-75 ℃ (dry ice/methanol bath) solution of 4-fluoro-3-isopropyl-1- (triisopropylsilyl) -1H-indole (0.910g, 2.73mmol) and 1, 1, 4, 7, 7-pentamethyldiethylenetriamine (0.572mL, 2.73mmol) in THF (13.64mL) in an oven-dried 50mL recovery flask under a nitrogen atmosphere. The solution was stirred at-75 ℃ for 6.5h and held for 6 h. 1, 2-dibromotetrafluoroethane (0.325mL, 2.73mmol) was then added to the reaction mixture. The solution was stirred at-75 ℃ for 10min, then warmed to room temperature. The reaction progressed by 50%. The excess solvent was evaporated from the reaction mixture. The resulting orange oil was taken up in DCM (total volume about 4mL) and purified by flash chromatography on a 24g silica gel column eluting with hexane. The product and the remaining starting indole co-eluted. The fractions were combined and the excess solvent was evaporated to give 5-bromo-4-fluoro-3-isopropyl-1- (triisopropylsilyl) -1H-indole (1.07g, 1.68mmol, 65% yield) and 4-fluoro-3-isopropyl-1- (triisopropylsilyl) -1H-indole as a mixture in a clear colorless liquid. The mixed product is directly used continuously. LCMS MH +: 412.08. HPLC retention time 1.50 min. Method G.
Intermediate 991D: 4- (4-fluoro-3-isopropyl-1- (triisopropylsilyl) -1H-indol-5-yl) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester
Figure BDA0001979596660003062
5-bromo-4-fluoro-3-isopropyl-1- (triisopropylsilyl) -1H-indole (650mg, 1.576mmol) was dissolved in THF (7880 μ l) in a 40mL scintillation vial with a red pressure release cap and containing a Teflon coated stir bar. To a vial was added 4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (585mg, 1.891mmol) followed by potassium phosphate (2364. mu.l, 4.73 mmol). The reaction mixture was degassed by bubbling nitrogen through the solution for 5min, and then the 2 nd generation XPhos precatalyst (31.0mg, 0.039mmol) was added to the reaction mixture. The clear yellow reaction mixture was placed under nitrogen and heated to 60 ℃ with stirring and held for 6 h. The reaction mixture was cooled to room temperature. The aqueous phase was removed and the excess THF was evaporated from the reaction mixture. The resulting oily residue was taken up in DCM (total volume about 4mL) and purified by flash chromatography eluting with ethyl acetate and hexane. The product fractions were concentrated and evacuated to give 4- (4-fluoro-3-isopropyl-1- (triisopropylsilyl) -1H-indol-5-yl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester as a pale yellow viscous solid (0.65g, 1.14mmol, 72.6% yield). 1H NMR (400MHz, chloroform-d) δ 7.18(d, J ═ 8.6Hz, 1H), 6.99-6.94(m, 1H), 6.92(s, 1H), 5.90(br s, 1H), 4.10(br s, 2H), 3.66(br t, J ═ 5.2Hz, 2H), 3.36(spt, J ═ 6.8Hz, 1H), 2.61(br s, 2H), 1.53(s, 9H), 1.35(d, J ═ 6.7Hz, 6H), 1.16(d, J ═ 7.6Hz, 18H). LCMS MH+: 515.5. HPLC retention time 1.53 min. Method G.
Intermediate 991E: 4- (4-fluoro-3-isopropyl-1- (triisopropylsilyl) -1H-indol-5-yl) piperidine-1-carboxylic acid tert-butyl ester
Figure BDA0001979596660003071
Palladium on 5% carbon (100mg, 1.271mmol) was weighed into a 20mL flash containing a Teflon coated stir bar and a red pressure release capScintillation vial. Tert-butyl 4- (4-fluoro-3-isopropyl-1- (triisopropylsilyl) -1H-indol-5-yl) -5, 6-dihydropyridine-1 (2H) -carboxylate (654.4mg, 1.271mmol) was dissolved in MeOH (12.71mL) under a nitrogen atmosphere and transferred to a vial containing palladium on carbon. Ammonium formate (401mg, 6.36mmol) was added to the reaction mixture and the vial was capped. The reaction mixture was stirred at 50 ℃ for 4 h. Additional ammonium formate (401mg, 6.36mmol) was added to the reaction mixture and the reaction mixture was stirred at 60 ℃ for 3h, but not to completion. The reaction mixture was stirred at 50 ℃ overnight. The reaction mixture was filtered through celite to remove Pd/C. Evaporation of excess methanol from the reaction mixture gave tert-butyl 4- (4-fluoro-3-isopropyl-1- (triisopropylsilyl) -1H-indol-5-yl) piperidine-1-carboxylate (654mg, 1.271mmol, 100% yield, 30% purity) as a clear pale yellow oil. By passing 1The product was checked by H NMR and was about 30% reduced and 70% starting olefin. LCMS MH+: 517.5. HPLC retention time 1.53 min. Method G.
Intermediate 991F: 4- (4-fluoro-3-isopropyl-1H-indol-5-yl) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester
Figure BDA0001979596660003081
In a 20mL scintillation vial tert-butyl 4- (4-fluoro-3-isopropyl-1- (triisopropylsilyl) -1H-indol-5-yl) -3, 6-dihydropyridine-1 (2H) -carboxylate (0.650g, 1.263mmol) (7: 3 mixture of piperidinoalkene and piperidinoalkane) and tetra-n-butylammonium fluoride (0.660g, 2.53mmol) were dissolved in THF (6.31 mL). The reaction mixture was stirred at room temperature for 10 min. Reaction completion, with 2 peaks corresponding to product olefin (1.15min, M + H)+359.3) and alkanes (1.16min, M + H)+359.3, 361.3). The reaction mixture was partitioned between brine and ethyl acetate (1: 1, total volume about 16 mL). The phases were separated and the aqueous phase was extracted with ethyl acetate (2X 4 mL). The combined organic phases were washed with brine (2 × 5mL), dried over sodium sulfate and filtered. The excess solvent was evaporated from the organic phase to give 4- (4-fluoro-3-isopropyl-1H-indol-5-yl) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester as a pale yellow oilEster (0.476g, 1.263 mmol). LCMS MH+: 359.3. HPLC retention time 1.15 min. Method G.
Intermediate 991G: 4- (4-fluoro-3-isopropyl-1H-indol-5-yl) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester
Figure BDA0001979596660003082
5% Palladium on carbon (150mg, 1.264mmol) was weighed into a 20mL scintillation vial containing a Teflon coated stir bar and a red pressure release cap. Tert-butyl 4- (4-fluoro-3-isopropyl-1H-indol-5-yl) -5, 6-dihydropyridine-1 (2H) -carboxylate (453mg, 1.264mmol) was dissolved in MeOH (6.32mL) under a nitrogen atmosphere and transferred to a vial containing palladium on carbon. Ammonium formate (797mg, 12.64mmol) was added to the reaction mixture and the vial was capped. The reaction mixture was stirred at 60 ℃ for 30 min. The reaction was complete. The reaction mixture was filtered through celite to remove Pd/C. The excess methanol was evaporated from the reaction mixture. The resulting yellow oil was taken up in DCM (3mL) and purified by flash chromatography on a 24g silica gel column eluting with ethyl acetate and hexanes to give tert-butyl 4- (4-fluoro-3-isopropyl-1H-indol-5-yl) piperidine-1-carboxylate (370.3mg, 1.017mmol, 80% yield) as a white crystalline solid.1H NMR (400MHz, chloroform-d) δ 7.96(br s, 1H), 7.10(d, J ═ 8.4Hz, 1H), 7.02-6.97(m, 1H), 6.93(d, J ═ 2.1Hz, 1H), 4.28(br s, 2H), 3.37(spt, J ═ 6.8Hz, 1H), 3.17(tt, J ═ 12.0, 3.6Hz, 1H), 2.88(br, J ═ 11.3, 2H), 1.89-1.81(m, 2H), 1.81-1.68(m, 2H), 1.52(s, 9H), 1.36(d, J ═ 6.8Hz, 6H). LCMS MH +: 361.3. HPLC retention time 1.16 min. Method G.
Intermediate 991H: 5- (1- (tert-Butoxycarbonyl) piperidin-4-yl) -4-fluoro-3-isopropyl-1H-indole-1-carboxylic acid tert-butyl ester
Figure BDA0001979596660003091
In a 20mL vial containing a Teflon coated stir barTert-butyl 4- (4-fluoro-3-isopropyl-1H-indol-5-yl) piperidine-1-carboxylate (370mg, 1.026mmol) and di-tert-butyl dicarbonate (540. mu.l, 2.258mmol) were dissolved in THF (5132. mu.l). Then 4-dimethylaminopyridine (12.54mg, 0.103mmol) was added. The vial was capped and the clear pale yellow solution was stirred at room temperature for 2 h. The reaction was complete. The excess solvent was evaporated from the reaction mixture. The residue was taken up in DCM (ca 2mL) and purified by flash chromatography on a 24g silica gel column eluting with ethyl acetate and hexanes to give 5- (1- (tert-butoxycarbonyl) piperidin-4-yl) -4-fluoro-3-isopropyl-1H-indole-1-carboxylic acid tert-butyl ester as a white foam (4.57g, 0.98mmol, 99% yield).1H NMR (400MHz, chloroform-d) δ 7.85(br s, 1H), 7.28(br s, 1H), 7.12(dd, J ═ 8.4, 7.2Hz, 1H), 3.29(spt, J ═ 6.8Hz, 1H), 3.14(tt, J ═ 12.0, 3.5Hz, 1H), 2.87(br t, J ═ 11.4Hz, 2H), 1.88-1.79(m, 2H), 1.51(s, 9H), 1.34(d, J ═ 6.8Hz, 6H). LCMS MH +: 461.4. HPLC retention time 1.36 min. Method G.
Intermediate 991I: 5- (1- (tert-Butoxycarbonyl) piperidin-4-yl) -4-fluoro-3-isopropyl-2- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-indole-1-carboxylic acid tert-butyl ester
Figure BDA0001979596660003092
In a 20mL vial containing a Teflon coated stir bar, tert-butyl 5- (1- (tert-butoxycarbonyl) piperidin-4-yl) -4-fluoro-3-isopropyl-1H-indole-1-carboxylate (456.7mg, 0.992mmol) and 2-isopropoxy-4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane (324. mu.l, 1.587mmol) were dissolved in THF (7933. mu.l). The vial was cooled to-20 ℃ (dry ice/NMP bath) under a nitrogen atmosphere. Lithium diisopropylamide (992. mu.l, 1.983mmol) was added dropwise (via syringe through the septum cap) over about 5min to the vial. The reaction mixture was stirred at-20 ℃ for 1h, then slowly warmed to 0 ℃. Most of the starting material (about 75%) was converted to product. The reaction mixture was warmed to 10 ℃ and then purified by the addition of 1M KHSO4Quench (5 mL). The resulting mixture was extracted with EtOAc (2X 3 mL). Incorporated by referenceThe organic extracts were washed with brine (2X 3mL) and the excess solvent was evaporated. The residue was taken up in DCM (2mL) and purified by flash chromatography on a 24g silica gel column eluting with ethyl acetate and hexanes to give tert-butyl 5- (1- (tert-butoxycarbonyl) piperidin-4-yl) -4-fluoro-3-isopropyl-2- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-indole-1-carboxylate (468.9mg, 0.72mmol, 72.6% yield, 90% purity) as a white solid. 1H NMR (400MHz, chloroform-d) δ 7.61(d, J ═ 8.6Hz, 1H), 7.06(dd, J ═ 8.4, 7.1Hz, 1H), 4.28(br s, 2H), 3.35-3.26(m, 1H), 3.14(br s, 1H), 2.87(br t, J ═ 11.9Hz, 2H), 1.88-1.81(m, 2H), 1.71(br s, 2H), 1.67(s, 9H), 1.44(s, 12H). LCMS MH+-56: 531.4. HPLC retention time 1.39 min. Method G.
Intermediate 991J: 5- (1- (tert-Butoxycarbonyl) piperidin-4-yl) -2- (8-ethyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -4-fluoro-3-isopropyl-1H-indole-1-carboxylic acid tert-butyl ester
Figure BDA0001979596660003101
5- (1- (tert-Butoxycarbonyl) piperidin-4-yl) -4-fluoro-3-isopropyl-2- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-indole-1-carboxylic acid tert-butyl ester (100mg, 0.170mmol) and 6-bromo-8-methoxy- [1, 2, 4-methoxy-1]Triazolo [1, 5-a]Pyridine (42.8mg, 0.188mmol) was weighed into a 1 dram vial with a red pressure release cap and containing a teflon-coated stir bar. The vial was charged with THF (852. mu.l) and potassium phosphate (170. mu.l, 0.511mmol) and the reaction mixture was degassed by bubbling nitrogen through the reaction mixture for 3 min. A vial was charged with 2 nd generation XPhos pre-catalyst (4.02mg, 5.11 μmol) and the reaction mixture was placed under a nitrogen atmosphere and stirred at 60 ℃ overnight. The reaction was complete. The aqueous phase is removed and the excess solvent is evaporated from the organic phase. The resulting orange residue was taken up in DCM (ca. 3mL) and purified by flash chromatography on a 12g silica gel column eluting with ethyl acetate and hexanes to give 5- (1- (tert-butoxycarbonyl) piperidin-4-yl) -4-fluoro-3-isopropyl-2-one as a cloudy colorless glass (8-methoxy- [1, 2, 4 ]]Triazolo [1, 5-a]Pyridin-6-yl) -1H-indole-1-carboxylic acid tert-butyl ester (100.7mg, 0.124mmol, 72.9% yield, 75% purity).1H NMR (400MHz, chloroform-d) δ 8.36(s, 1H), 8.22(d, J ═ 1.1Hz, 1H), 8.04(d, J ═ 8.7Hz, 1H), 7.28(s, 1H), 7.23(dd, J ═ 8.6, 7.2Hz, 1H), 6.72(d, J ═ 1.0Hz, 1H), 4.39-4.22(m, 2H), 4.04(s, 3H), 3.19(tt, J ═ 12.0, 3.3Hz, 1H), 2.99(dtd, J ═ 14.1, 7.0, 3.0Hz, 1H), 2.88(br t, J ═ 11.2Hz, 2H), 1.91-1.82(m, 2H), 1.74(br, 12, 3.5, 1H), 1.24H (H, 24H), 1.24H, 15H, 1H). LCMS MH+: 608.6. HPLC retention time 1.22 min. Method G.
Example 991:
5- (1- (tert-Butoxycarbonyl) piperidin-4-yl) -4-fluoro-3-isopropyl-2- (8-methoxy- [1, 2, 4) by reaction with 2: 1 trifluoroacetic acid/dichloromethane (1.2mL, 0.041mmol) in a 1 dram vial for 30min]Triazolo [1, 5-a]Pyridin-6-yl) -1H-indole-1-carboxylic acid tert-butyl ester (25mg, 0.041mmol) was Boc deprotected. Toluene (about 0.15mL) was added and then the excess solvent was evaporated from the reaction mixture. The resulting residue was stirred with 2-chloro-N, N-dimethylacetamide (10.00mg, 0.082mmol) and potassium carbonate (28.4mg, 0.206mmol) in NMP (0.411mL) at 22 ℃ for 1.5 h. The reaction was not completed. The reaction mixture was stirred at 22 ℃ over the weekend. The reaction was complete. The reaction mixture was partitioned between water and ethyl acetate (total volume 3mL) and the aqueous phase was extracted with ethyl acetate (2 × 1 mL). The excess solvent was evaporated from the combined organic extracts. To the resulting residue was added DMF (about 1.5 mL). The crude material was purified via preparative LC/MS using the following conditions: column: XBridge C18, 19 × 200mm, 5 μm particles; mobile phase A: 5: 95 acetonitrile: water +10mM ammonium acetate; mobile phase B: 95: 5 acetonitrile: water +10mM ammonium acetate; gradient: 15-55% B over 20 minutes, followed by 4 minutes at 100% B; flow rate: 20 mL/min. The fractions containing the desired product were combined and dried by centrifugal evaporation to give 2- (4- (4-fluoro-3-isopropyl-2- (8-methoxy- [1, 2, 4) ]Triazolo [1, 5-a]Pyridin-6-yl) -1H-indol-5-yl) piperidin-1-yl) -N, N-dimethylacetamide (8.5mg, 0.017mmol, 42.1% yield).1H NMR(500MHz，DMSO-d6)δ11.44(br s，1H)，8.58(s，1H)，8.54-8.47(m，1H)，7.18(br d，J＝8.5Hz，1H)，7.13(s，1H)，7.09(t，J＝7.0Hz，1H)，4.06(s，3H)，3.30(br s，1H)，3.17(s，2H)，3.07(s，3H)，3.01-2.88(m，3H)，2.88-2.78(m，3H)，2.20(br t，J＝10.5Hz，3H)，1.83-1.75(m，3H)，1.73(br s，4H)，1.36(br d，J＝6.4Hz，6H)。LCMS MH+: 493. HPLC retention time 1.30 min. Method QC-ACN-AA-XB.
The following examples were prepared in a similar manner to that described in example 991.
Watch 26
Figure BDA0001979596660003111
Figure BDA0001979596660003121
Example 994
4- (3-isopropyl-2- (8-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) -1H-indol-5-yl) piperidine-1-carboxamidine
Figure BDA0001979596660003122
Mixing 6- (3-isopropyl-5- (piperidine-4-yl) -1H-indol-2-yl) -8-methyl- [1, 2, 4]Triazolo [1, 5-a]Pyridine (15.77mg, 0.042mmol) was stirred with 1H-pyrazole-1-carboxamidine (5.81mg, 0.053mmol) and DIPEA (0.037mL, 0.211mmol) in DMF (0.422mL) at 75 ℃ for 8H. DMF (1mL) was added to the reaction mixture and the reaction mixture was purified via preparative LC/MS using the following conditions: column: XBridge C18, 19 × 200mm, 5 μm particles; mobile phase A: 5: 95 acetonitrile: water +10mM ammonium acetate; mobile phase B: 95: 5 acetonitrile: water +10mM ammonium acetate; gradient: 15-55% B over 19 minutes, followed by 5 minutes at 100% B; flow rate: 20 mL/min. The product-containing fractions were combined and dried by centrifugal evaporation to give 4- (3-isopropyl-2- (8-methyl- [1, 2, 4) ]Triazolo [1, 5-a]Pyridin-6-yl) -1H-Indol-5-yl) piperidine-1-carboxamidine (8.4mg, 0.019mmol, 45.0% yield). LCMS MH+: 416.2. HPLC retention time 1.23 min. Method QC-ACN-AA-XB.1H NMR(500MHz，DMSO-d6)δ9.29(s，1H)，8.39(s，1H)，7.99(s，1H)，7.33-7.33(m，1H)，7.31(d，J＝7.9Hz，1H)，7.15(s，1H)，7.11(br d，J＝8.1Hz，1H)，2.99-2.88(m，3H)，2.79(s，2H)，2.77-2.70(m，1H)，2.16-2.06(m，1H)，1.74-1.64(m，2H)，1.51(s，4H)，1.50-1.40(m，2H)，1.08-0.98(m，6H)。
Biological assay
The pharmacological properties of the compounds of the present application can be demonstrated by a variety of bioassays. The following exemplary bioassays have been performed with the compounds of the present application.
TLR7/8/9 inhibition reporter assay
HEK-Blue overexpressing human TLR7, TLR8 or TLR9 receptor using inducible SEAP (secretory embryo alkaline phosphatase) reporter gene under control of IFN-beta minimal promoter fused to 5 NF-kappa B and AP-1 binding sitesTMCells (Invivogen) were used to screen for inhibitors of these receptors. Briefly, cells were seeded into Greiner 384-well plates (15000 cells/well for TLR7, 20,000 cells/well for TLR8, and 25,000 cells/well for TLR 9) and subsequently treated with test compounds in DMSO to give final dose response concentrations ranging from 0.05nM to 50 μ M. After 30 min of pretreatment with compounds at room temperature, cells were stimulated with either TLR7 ligand (gardiquimod at a final concentration of 7.5 μ M), TLR8 ligand (R848 at a final concentration of 15.9 μ M), or TLR9 ligand (ODN 2006 at a final concentration of 5 nM) to activate NF- κ B and AP-1, which in turn induced SEAP production. At 37 ℃ in 5% CO 2After a further 22 h incubation, HEK-Blue was added by adding it according to the manufacturer's instructionsTMDetection reagent (Invivogen), a cell culture medium that allows for detection of SEAP, determines SEAP levels. % inhibition was determined as the% reduction in HEK-Blue signal present in wells treated with agonist + DMSO alone compared to wells treated with known inhibitors.
TABLE 27 TLR7/8/9 reporter assay data
Figure BDA0001979596660003131
Figure BDA0001979596660003141
Figure BDA0001979596660003151
Figure BDA0001979596660003161
Figure BDA0001979596660003171
Figure BDA0001979596660003181
Figure BDA0001979596660003191
Figure BDA0001979596660003201
Figure BDA0001979596660003211
Figure BDA0001979596660003221
Figure BDA0001979596660003231
Suppressing data
In vivo mouse TLR7 PD model:
adult male C57BL/6 mice were used for the experiments. Mice (7 to 10/group) were randomized into different treatment groups based on body weight. Mice from each treatment group were dosed orally with vehicle or test compound. Mice were stimulated 30min after oral administration of vehicle or test compound by intraperitoneal injection of gardiquimod for the TLR7 PD model. At 90 minutes after injection of gardiquimod, mice were bled under isoflurane anesthesia and plasma IL-6 and IFN- α levels were assessed by using a commercially available ELISA kit (BD Biosciences, PBL Life Sciences). At the end of the experiment, mean cytokine data were plotted and one-way ANOVA and Dunnett's tests were performed to calculate the significance of the test compound treated groups relative to the vehicle control group. The% inhibition of cytokine induction by the test compound-treated group relative to the vehicle control group was calculated. Data from multiple studies with different test compounds are shown in table 28.
TABLE 28 inhibition of IL-6 and IFN- α in the mouse TLR7 PD model%
Figure BDA0001979596660003232
Figure BDA0001979596660003241
NZB/W model of Systemic Lupus Erythematosus (SLE):
female NZB/W mice were screened and randomized based on anti-dsDNA antibody titers and urinary NGAL (neutrophil gelatinase-associated lipocalin). Mice were orally treated with vehicle or test compound once daily for 24 weeks. The effect of the test compounds on disease severity was evaluated by measuring endpoints including proteinuria, urinary NGAL, urinary TIMP1, Blood Urea Nitrogen (BUN), anti-dsDNAAb titers, anti-smRNPAb titers, and plasma IL10 and IL12p40 levels. The absolute increase in BUN was measured as follows: deduction in processing from BUN value evaluated after completion of processingBUN values evaluated before start. At the end of the experiment, by CO2Asphyxiation all mice were euthanized and kidney samples were used for histology. To calculate the significance of the test compound treated groups relative to the vehicle control group, one-way ANOVA and Dunnett's tests were performed. The% reduction in disease severity for the test compound treated groups relative to the vehicle control group was calculated for each parameter. Cumulative disease scores and% reduction in cumulative disease scores were calculated by considering the average inhibition on proteinuria, urinary NGAL, anti-dsDNAAb titers and anti-smAb titers to reflect the effect on overall severity of disease progression. Data from multiple studies with different test compounds are shown in table 30.
Figure BDA0001979596660003251

Claims (10)

1. A compound of formula (I) or a salt thereof:
Figure FDA0003062979780000011
wherein
R1is-CH2CH3、-CH(CH3)2or-CH2CHF2；
Each R2Independently of each other is F, Cl, -CN, -CH3、-CH2CH3、-CH(CH3)2、-CF3、-CH2CN、-CH2OH、-CH2CH2OH、-CH(CH3)OH、-C(CH3)2OH、-OCH2CH2OH、-OCH3、-OCH2CH3、-OCH2CH(CH3)2、-OCHF2、-CH2OCH3、-CH2OCH2CH3、-OCH2CH2OC(O)CH3、-NH2、-NH(CH2CH3)、-NH(CH2CF3)、-NH(CH2C(CH3)2OH)、-NHCH2(phenyl), -NHS (O)2(cyclopropyl), cyclopropyl, morpholinyl, dioxothiomorpholinyl or methylpiperazinyl;
R3is H, C1-5Alkyl radical, C2-3Fluoroalkyl radical, C1-3Cyanoalkyl, C2-5Hydroxyalkyl, -CH2CH2OCH3、-CH2N(CH3)2、-CH2CH2NH(CH3)、-C＝N(NH2)、-C(O)CH3、-C(O)CH(CH2CH3)2、-C(O)CH2CF3、-C(O)CH2CH2OH、-C(O)CH(CH3)OH、-C(O)CH2CH(CH3)OH、-C(O)CH2C(CH3)2OH、-C(O)CH2CN、-C(O)CH2CH2CN、-C(O)OC(CH3)3、-C(O)CH2OCH3、-C(O)CH2CH2OCH3、-C(O)OCH2CH2NH2、-C(O)OCH2CH2N(CH3)2、-C(O)OCH2CH2N(CH2CH3)2、-C(O)CH2S(O)2CH3、-C(O)CH2CH2S(O)2CH3、-C(O)CH2NHS(O)2CH3、-C(O)NH(CH2C(CH3)3)、-C(O)CH2NH(CH3)、-C(O)CH2NH(CH2CH3)、-C(O)CH2NH(CH2CH2CH3)、-C(O)CH2NH(CH(CH3)2)、-C(O)CH2NH(CH2CH(CH3)2)、-C(O)CH2NH(C(CH3)3)、-C(O)CH2N(CH3)2、-C(O)CH2N(CH3)(CH2CH3)、-C(O)CH2N(CH3)(CH2CH2CH3)、-C(O)CH2N(CH3)(CH(CH3)2)、-C(O)CH2N(CH3)(CH2CH(CH3)2)、-C(O)CH2N(CH2CH3)2、-C(O)CH2CH2NH(CH3)、-C(O)CH2CH2NH(CH2CH3)、-C(O)CH2CH2NH(CH2CH2CH3)、-C(O)CH2CH2NH(CH(CH3)2)、-C(O)CH2CH2NH(CH2C(CH3)3)、-C(O)CH2CH2N(CH3)2、-C(O)CH2CH2N(CH3)(CH2CH3)、-C(O)CH2CH2N(CH3)(CH2CH2CH3)、-C(O)CH2CH2N(CH3)(CH(CH3)2)、-C(O)CH(CH3)NH(CH3)、-C(O)CH2NH(CH2CN)、-C(O)CH2N(CH3)(CH2CH2CN)、-C(O)CH2NH(CH2C(O)NH2)、-C(O)CH2N(CH3)(CH2C(O)N(CH3)2)、-C(O)CH2CH2NH(CH2C(O)NH2)、-C(O)CH2CH2N(CH3)CH2C(O)N(CH3)2、-C(O)CH2NH(CH2CH2OH)、-C(O)CH2N(CH3)(CH2CH2OH)、-C(O)CH2CH2NH(CH2CH2OH)、-C(O)CH2CH2N(CH3)(CH2CH2OH)、-C(O)CH2NH(CH2CH2F)、-C(O)CH2NH(CH2CF3)、-C(O)CH2CH2NH(CH2CH2F)、-C(O)CH2NH(CH2CH2OCH3)、-C(O)CH2N(CH3)(CH2CH2OCH3)、-C(O)CH2CH2NH(CH2CH2OCH3)、-C(O)CH2CH2N(CH3)(CH2CH2OCH3)、-C(O)CH2N(CH2CH2OCH3)2、-C(O)CH2CH2CH2S(O)2NH2、-CH2C(O)NH2、-CH2C(O)NH(CH3)、-CH2C(O)N(CH3)2、-CH2C(O)NH(CH2CH3)、-CH2C(O)N(CH3)(CH2CH3)、-CH2C(O)N(CH2CH3)2、-CH2C(O)NH(CH2CH2CH3)、-CH2C(O)NH(CH(CH3)2)、-CH(CN)C(O)N(CH3)2、-CH2C(O)NH(CH2CH2CF3)、-CH2C(O)N(CH3)(CH2CH2OH)、-CH2C(O)N(CH3)(CH2CH2OH)、-CH2C(O)N(CH2CH3)(CH2CH2OH)、-CH2C(O)N(CH2CH2CH3)(CH2CH2OH)、-CH2C(O)N(CH3)(CH2CH2CH2OH)、-CH2C(O)NH(CH2C(CH3)2OH)、-CH2C(O)N(CH2CH(CH3)CH2CH3)(CH2CH2OH)、-CH2C(O)NH(CH2CH2CN)、-CH2C(O)N(CH3)(CH2CH2CN)、-CH2C(O)N(CH3)(CH2CH2OCH3)、-CH(CH3)CH2S(O)2(CH2CH2CH2CH3)、-CH2CH2S(O)2NH2、-CH2CH2S(O)2NH(CH3)、-CH2CH2S(O)2N(CH3)2、-CH(CH3)CH2S(O)2N(CH2CH3)2、-CH2CH2NHS(O)2CH3、-CH2CH2N(CH3)S(O)2CH3、-CH2C(O)NH(CH2CH2SCH3)、-C(O)NH(CH2CH2NH2)、-C(O)N(CH3)CH2CH2NH2、-C(O)NH(CH2CH2N(CH3)2)、-C(O)NH(CH2CH2CH2NH2)、-CH2CH2S(O)2CH3、-CH2CH2CH2S(O)2CH3、-CH(CH3)CH2S(O)2CH3、-C(O)CH2(2-oxa-6-azaspiro [3.3 ]]Heptyl), -C (O) CH2(piperazinonyl), -C (O) CH2(piperazinyl), -C (O) CH2(piperidinyl), -C (O) CH2(pyrimidinyl), -C (O) CH2(pyrrolidinyl), -C (O) CH2(tetrahydropyranyl) -, -C (O) CH2(tetrazolyl), -C (O) CH2(thiazolyl), -C (O) CH2CH2(azepanyl), -C (O) CH2CH2(azetidinyl), -C (O) CH2CH2(dioxothiomorpholinyl), -C (O) CH2CH2(morpholinyl), -C (O) CH2CH2(piperidonyl), -C (O) CH2CH2(piperidinyl), -C (O) CH2CH2(pyrrolidinonyl), -C (O) CH2CH2(pyrrolidinyl), -C (O) CH2CH(CH3) (oxetanyl), -C (O) NH (piperidinyl), -C (O) NH (pyrrolidinyl), -C (O) CH2NH (cyclopropyl), -C (O) CH2NH (cyclobutyl), -C (O) CH2NH (cyclohexyl), -C (O) CH2NH (oxetanyl), -C (O) CH2N(CH3) (cyclopropyl), -C (O) CH2N(CH3) (cyclohexyl), -C (O) CH2CH2NH (cyclopentyl), -C (O) CH2CH2NH (cyclohexyl), -C (O) CH2CH2N(CH3) (cyclohexyl), -C (O) CH2N(CH2CH2OH) (cyclopropyl), -C (O) CH2CH2N(CH2CH2OH) (cyclopropyl), -C (O) CH 2CH2NH(CH2(cyclopropyl)), -C (O) CH2CH2NH(CH2(tetrahydrofuryl)), -C (O) CH2NH(CH2(cyclopropyl)), -C (O) CH2NH(CH2(cyclohexyl)), -C (O) CH2NH(CH2(tetrahydrofuryl)), -C (O) NH (CH)2(piperidinyl)), -C (O) NH (CH)2(pyrrolidinyl)), -C (O) NH (CH)2CH2(morpholinyl)), -C (O) NH (CH)2CH2(piperazinyl)), -C (O) NH (CH)2CH2(piperidinyl)), -C (O) NH (CH)2CH2(pyrrolidinyl)), -C (O) O (azetidinyl), -C (O) O (piperidinyl), -C (O) O (pyrrolidinyl), -C (O) OCH2(azetidinyl), -C (O) OCH2(piperidinyl), -C (O) OCH2(pyrrolidinyl), -C (O) OCH2CH2(dioxothiomorpholinyl), -C (O) OCH2CH2(imidazolyl), -C (O) OCH2CH2(morpholinyl), -C (O) OCH2CH2(piperazinyl), -C (O) OCH2CH2(piperidinyl), -C (O) OCH2CH2(pyrrolidinyl), -CH2(cyclopropyl), -CH2(dioxotetrahydrothiopyran group), -CH2(imidazolyl), -CH2(isoxazolyl), -CH2(morpholinyl), -CH2(oxadiazolyl), -CH2(oxazolyl), -CH2(oxetanyl), -CH2(phenyl), -CH2(pyrazinyl), -CH2(pyrazolyl), -CH2(pyridazinyl), -CH2(pyrimidinyl), -CH2(tetrazolyl), -CH2(thiadiazolyl), -CH2(thiazolyl), -CH2(triazolonyl), -CH2(triazolyl), -CH (CH)3) (pyrazolyl), -CH (CH)3) (pyridazinyl), -CH (CH)3) (pyrimidinyl), -CH2CH2(dioxoisothiazolidinyl), -CH (CN) (oxetanyl), -CH (CH) 3)CH2S(O)2(morpholinyl), -CH (CH)3)CH2S(O)2(piperidinyl), -CH2C (O) (morpholinyl), -CH2C (O) (2-oxa-6-azaspiro [3.3 ]]Heptyl), -CH2C (O) (azetidinyl), -CH2C (O) (thiadiazinyl dioxide), -CH2C (O) (two)Oxi-thiazolidinyl), -CH2C (O) (thiomorpholinyl sulfate), -CH2C (O) (dioxothiomorpholinyl), -CH2C (O) (piperazinonyl), -CH2C (O) (piperazinyl), -CH2C (O) (piperidinyl), -CH2C (O) (pyrrolidinyl), -CH2C(O)NHCH(CH2CH2OH) (cyclopropyl), -CH2C(O)N(CH2CH2OH) (cyclopropyl), -CH2C(O)N(CH3) (cyclopropyl), -CH2C(O)N(CH3) (tetrahydrofuryl), -CH2C(O)N(CH3) (tetrahydropyranyl) -, -CH2C(O)N(CH3)CH2CH2(cyclopentyl), -CH2C(O)N(CH3)CH2CH2(pyrazolyl), -CH2C (O) NH (azetidinyl), -CH2C(O)NH(CH2(oxetanyl)), -CH2C (O) NH (cyclobutyl), -CH2C (O) NH (cyclopropyl), -CH2C (O) NH (oxetanyl), -CH2C (O) NH (tetrahydropyranyl), -CH2CH2S(O)2(morpholinyl) or-CH2CH2S(O)2(phenyl);
m is 0;
n is 0; and
p is 0, 1 or 2.
2. The compound of claim 1 or a salt thereof, wherein
R1is-CH (CH)3)2；
Each R2Independently is-CH3、-OCH3or-CH2OCH3；
R3Is H, -CH (CH)3)2、-CH2CH(CH3)2、-CH2CN、-CH2CH2CN、-CH2CH2CH2CN、-CH2C(CH3)2OH、-C(O)CH3、-C(O)CH(CH2CH3)2、-C(O)CH2OCH3、-C(O)CH2CH2OCH3、-C(O)CH2CH(CH3)OH、-C(O)CH2CN、-C(O)CH2CH2CN、-C(O)CH(CH3)NH(CH3)、-C(O)CH2NH(CH3)、-C(O)CH2N(CH3)2、-C(O)CH2NHCH2CH2CH3、-C(O)CH2NHCH(CH3)2、-C(O)CH2NHC(CH3)3、-C(O)CH2N(CH3)CH(CH3)2、-C(O)CH2NHCH2CH2OCH3、-CH2C(O)NH2、-CH2C(O)NH(CH3)、-CH2C(O)N(CH3)CH2CH3、-CH2C(O)NHCH2CH2CH3、-CH2C(O)NH(CH(CH3)2)、-CH2C(O)N(CH3)2、-CH2C(O)N(CH2CH3)2、-CH2CH2S(O)2CH3、-CH2CH2S(O)2NH2、-CH2C (O) NH (cyclobutyl), -CH2C (O) NH (cyclopropyl), -CH2C(O)N(CH3) (cyclopropyl), -CH2(oxazolyl), -CH2(pyrazolyl), -CH2(tetrazolyl), -CH2(triazolyl), -CH2C (O) (2-oxa-6-azaspiro [3.3 ]]Heptyl), -CH 2C (O) (azetidinyl), -CH2C (O) (thiadiazinyl dioxide), -CH2C (O) (thiomorpholinyl sulfate), -CH2C (O) (morpholinyl), -CH2C (O) (piperidinyl) or-CH2C (o) (pyrrolidinyl);
m is 0;
n is 0; and
p is 0, 1 or 2.
3. The compound of claim 1, or a salt thereof, wherein R3Is H, C1-5Alkyl radical, C2-3Fluoroalkyl radical, C1-3Cyanoalkyl or C2-5A hydroxyalkyl group.
4. The compound of claim 1 or a salt thereof, wherein
R1is-CH (CH)3)2；
Each R2Is independently selected from-CH3or-OCH3；
R3Is H, -CH2C(O)NH2、-CH2C(O)NH(CH3)、-CH2C(O)N(CH3)2or-CH2CH2S(O)2CH3；
m is 0;
n is 0; and
p is 1 or 2.
5. The compound of claim 1 or a salt thereof, wherein
R1is-CH (CH)3)2；
Each R2Independently selected from F, Cl, -CN, -CH3or-CF3；
R3is-CH2CN、-CH2C(CH3)2OH、-C(O)CH2NH(CH3)、-C(O)CH2N(CH3)2、-CH2C(O)N(CH3)2or-CH2CH2S(O)2CH3；
m is 0;
n is 0; and
p is 1 or 2.
6. A compound or salt thereof, wherein the compound is:
Figure FDA0003062979780000051
7. a compound or salt thereof, wherein the compound is:
Figure FDA0003062979780000052
8. a pharmaceutical composition comprising a compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
9. Use of a compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of autoimmune disease or chronic inflammatory disease.
10. The use of claim 9, wherein the autoimmune disease or chronic inflammatory disease is selected from the group consisting of Systemic Lupus Erythematosus (SLE), rheumatoid arthritis, Multiple Sclerosis (MS), and sjogren's syndrome.
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Families Citing this family (61)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10071079B2 (en) 2016-06-29 2018-09-11 Bristol-Myers Squibb Company [1,2,4]triazolo[1,5-a]pyridinyl substituted indole compounds
EP3490983B1 (en) 2016-07-30 2021-02-17 Bristol-Myers Squibb Company Dimethoxyphenyl substituted indole compounds as tlr7, tlr8 or tlr9 inhibitors
JP7028861B2 (en) 2016-09-09 2022-03-02 ブリストル－マイヤーズ スクイブ カンパニー Indole compound with pyridyl substitution
DK3526323T5 (en) 2016-10-14 2024-09-02 Prec Biosciences Inc MODIFIED MEGANUCLEASES SPECIFIC FOR A RECOGNITION SEQUENCE IN THE HEPATITIS B VIRUS GENOME
WO2019028302A1 (en) 2017-08-04 2019-02-07 Bristol-Myers Squibb Company Substituted indole compounds useful as inhibitors of tlr7/8/9
CN110997670B (en) * 2017-08-04 2022-11-01 百时美施贵宝公司 [1,2,4] triazolo [4,3-a ] pyridyl substituted indole compounds
WO2019099336A1 (en) * 2017-11-14 2019-05-23 Bristol-Myers Squibb Company Substituted indole compounds
KR20200100687A (en) 2017-12-15 2020-08-26 브리스톨-마이어스 스큅 컴퍼니 Substituted indole ether compounds
EA202091508A1 (en) * 2017-12-19 2020-09-14 Бристол-Маерс Сквибб Компани 6-AZAINDOL CONNECTIONS
KR20200101398A (en) 2017-12-19 2020-08-27 브리스톨-마이어스 스큅 컴퍼니 Amide substituted indole compounds useful as TLR inhibitors
ES2932361T3 (en) * 2017-12-19 2023-01-18 Bristol Myers Squibb Co Substituted Indole Compounds Useful as TLR Inhibitors
WO2019123340A1 (en) 2017-12-20 2019-06-27 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. 3'3' cyclic dinucleotides with phosphonate bond activating the sting adaptor protein
CA3086431A1 (en) 2017-12-20 2019-06-27 Bristol-Myers Squibb Company Amino indole compounds useful as tlr inhibitors
MX2020006014A (en) * 2017-12-20 2020-08-17 Bristol Myers Squibb Co Diazaindole compounds.
CN111511754B (en) 2017-12-20 2023-09-12 捷克共和国有机化学与生物化学研究所 2'3' cyclic dinucleotides with phosphonate bonds of activated STING adaptor protein
CN111491918B (en) 2017-12-20 2023-10-24 百时美施贵宝公司 Aryl and heteroaryl substituted indole compounds
CN111699187A (en) 2018-02-12 2020-09-22 豪夫迈·罗氏有限公司 Novel sulfone compounds and derivatives for the treatment and prevention of viral infections
JP7050165B2 (en) 2018-02-26 2022-04-07 ギリアード サイエンシーズ， インコーポレイテッド Substituted pyrrolidine compounds as HBV replication inhibitors
WO2019195181A1 (en) 2018-04-05 2019-10-10 Gilead Sciences, Inc. Antibodies and fragments thereof that bind hepatitis b virus protein x
TWI833744B (en) 2018-04-06 2024-03-01 捷克科學院有機化學與生物化學研究所 3'3'-cyclic dinucleotides
TW202005654A (en) 2018-04-06 2020-02-01 捷克科學院有機化學與生物化學研究所 2'2'-cyclic dinucleotides
TWI818007B (en) 2018-04-06 2023-10-11 捷克科學院有機化學與生物化學研究所 2'3'-cyclic dinucleotides
US11142750B2 (en) 2018-04-12 2021-10-12 Precision Biosciences, Inc. Optimized engineered meganucleases having specificity for a recognition sequence in the Hepatitis B virus genome
US20190359645A1 (en) 2018-05-03 2019-11-28 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. 2'3'-cyclic dinucleotides comprising carbocyclic nucleotide
EP3807270B1 (en) 2018-06-12 2023-09-13 F. Hoffmann-La Roche AG Novel heteroaryl heterocyclyl compounds for the treatment of autoimmune disease
US20210269451A1 (en) * 2018-06-13 2021-09-02 Hoffmann-La Roche Inc. Pyridinyl heterocyclyl compounds for the treatment of autoimmune disease
US11952363B2 (en) 2018-07-23 2024-04-09 Hoffmann-La Roche Inc. Piperazine compounds for the treatment of autoimmune disease
WO2020028097A1 (en) 2018-08-01 2020-02-06 Gilead Sciences, Inc. Solid forms of (r)-11-(methoxymethyl)-12-(3-methoxypropoxy)-3,3-dimethyl-8-0x0-2,3,8,13b-tetrahydro-1h-pyrido[2,1-a]pyrrolo[1,2-c] phthalazine-7-c arboxylic acid
CN112638908A (en) 2018-09-04 2021-04-09 豪夫迈·罗氏有限公司 Benzothiazoles for treatment of autoimmune diseases
CN112654618A (en) 2018-09-06 2021-04-13 豪夫迈·罗氏有限公司 Novel cyclic amidine compounds for the treatment of autoimmune diseases
CN112912382B (en) * 2018-10-24 2024-07-02 百时美施贵宝公司 Substituted indole dimer compounds
JP2022505707A (en) * 2018-10-24 2022-01-14 ブリストル－マイヤーズ スクイブ カンパニー Substituted indole and indazole compounds
EP3873608A1 (en) 2018-10-31 2021-09-08 Gilead Sciences, Inc. Substituted 6-azabenzimidazole compounds having hpk1 inhibitory activity
AU2019372046B2 (en) 2018-10-31 2022-05-26 Gilead Sciences, Inc. Substituted 6-azabenzimidazole compounds as HPK1 inhibitors
JP7350872B2 (en) 2019-03-07 2023-09-26 インスティチュート オブ オーガニック ケミストリー アンド バイオケミストリー エーエスシーアール，ヴイ．ヴイ．アイ． 3'3'-cyclic dinucleotide and its prodrug
EP3935065A1 (en) 2019-03-07 2022-01-12 Institute of Organic Chemistry and Biochemistry ASCR, V.V.I. 3'3'-cyclic dinucleotide analogue comprising a cyclopentanyl modified nucleotide as sting modulator
AU2020231201A1 (en) 2019-03-07 2021-08-26 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. 2'3'-cyclic dinucleotides and prodrugs thereof
TWI751516B (en) 2019-04-17 2022-01-01 美商基利科學股份有限公司 Solid forms of a toll-like receptor modulator
TW202212339A (en) 2019-04-17 2022-04-01 美商基利科學股份有限公司 Solid forms of a toll-like receptor modulator
US20220213099A1 (en) 2019-05-07 2022-07-07 Bristol-Myers Squibb Company Prodrug compounds
US20220289739A1 (en) * 2019-05-09 2022-09-15 Bristol-Myers Squibb Company Substituted benzimidazolone compounds
US11453681B2 (en) 2019-05-23 2022-09-27 Gilead Sciences, Inc. Substituted eneoxindoles and uses thereof
CN110146631B (en) * 2019-06-25 2021-11-12 山西康宝生物制品股份有限公司 Method for detecting residual quantity of polyethylene glycol monomethyl ether in medicinal material
EP4017476A1 (en) 2019-08-19 2022-06-29 Gilead Sciences, Inc. Pharmaceutical formulations of tenofovir alafenamide
CN117843811A (en) 2019-09-30 2024-04-09 吉利德科学公司 HBV vaccine and method of treating HBV
KR20220079587A (en) * 2019-10-04 2022-06-13 브리스톨-마이어스 스큅 컴퍼니 Substituted Carbazole Compounds
CN116057068A (en) 2019-12-06 2023-05-02 精密生物科学公司 Optimized engineered meganucleases with specificity for recognition sequences in hepatitis b virus genomes
AU2021237718B2 (en) 2020-03-20 2023-09-21 Gilead Sciences, Inc. Prodrugs of 4'-C-substituted-2-halo-2'-deoxyadenosine nucleosides and methods of making and using the same
JP2023530264A (en) 2020-06-11 2023-07-14 ブリストル－マイヤーズ スクイブ カンパニー TLR7 inhibitors in combination with prednisolone or hydroxychloroquine to treat cutaneous lupus erythematosus
BR112022025920A2 (en) 2020-06-22 2023-01-10 Bristol Myers Squibb Co TREATMENT OF RHEUMATOID ARTHRITIS
TW202214632A (en) * 2020-07-27 2022-04-16 大陸商江蘇恆瑞醫藥股份有限公司 Indole fused ring derivatives, their preparation method and medical use
MX2023006193A (en) 2020-11-26 2023-06-09 Jiangsu Hengrui Pharmaceuticals Co Ltd Fused tricyclic compound, preparation method therefor and application thereof in medicine.
US11661431B2 (en) 2021-04-16 2023-05-30 Gilead Sciences, Inc. Thienopyrrole compounds
WO2022241134A1 (en) 2021-05-13 2022-11-17 Gilead Sciences, Inc. COMBINATION OF A TLR8 MODULATING COMPOUND AND ANTI-HBV siRNA THERAPEUTICS
CN113416188B (en) * 2021-05-31 2022-12-13 河南偶联生物科技有限公司 Synthetic method of [1,2,4] triazolo [1,5-A ] pyridine compound
KR20240005901A (en) 2021-06-23 2024-01-12 길리애드 사이언시즈, 인코포레이티드 Diacylglycerol Kinase Modulating Compounds
WO2022271659A1 (en) 2021-06-23 2022-12-29 Gilead Sciences, Inc. Diacylglyercol kinase modulating compounds
WO2022271677A1 (en) 2021-06-23 2022-12-29 Gilead Sciences, Inc. Diacylglyercol kinase modulating compounds
US11976072B2 (en) 2021-06-23 2024-05-07 Gilead Sciences, Inc. Diacylglycerol kinase modulating compounds
EP4398989A1 (en) 2021-09-10 2024-07-17 Gilead Sciences, Inc. Thienopyrrole compounds
WO2024015825A1 (en) 2022-07-13 2024-01-18 Bristol-Myers Squibb Company Processes for preparing 5-bromo-3,4-dimethylpyridin-2-amine and 6-bromo-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008065198A1 (en) * 2006-12-01 2008-06-05 Galapagos N.V. Triazolopyridine compounds useful for the treatment of degenerative & inflammatory diseases
CN101977910A (en) * 2008-01-22 2011-02-16 赛诺菲-安万特 N-azabicyclic carboxamide derivatives, preparation thereof and therapeutic use thereof
CN102482273A (en) * 2009-06-26 2012-05-30 加拉帕戈斯股份有限公司 5-phenyl-[1,2,4 ]triazolo[1,5-a]pyridin-2-yl carboxamides as jak inhibitors

Family Cites Families (46)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6867200B1 (en) 1998-12-18 2005-03-15 Axys Pharmaceuticals, Inc. (Hetero)aryl-bicyclic heteroaryl derivatives, their preparation and their use as protease inhibitors
JP2007524615A (en) 2003-06-20 2007-08-30 コーリー ファーマシューティカル ゲーエムベーハー Low molecular weight Toll-like receptor (TLR) antagonist
WO2006113458A1 (en) * 2005-04-15 2006-10-26 Bristol-Myers Squibb Company Heterocyclic inhibitors of protein arginine methyl transferases
JP2009532501A (en) 2006-04-04 2009-09-10 ミリアド ジェネティクス， インコーポレイテッド Compounds for diseases and disorders
DE102006033109A1 (en) 2006-07-18 2008-01-31 Grünenthal GmbH Substituted heteroaryl derivatives
US8027888B2 (en) 2006-08-31 2011-09-27 Experian Interactive Innovation Center, Llc Online credit card prescreen systems and methods
WO2008152471A1 (en) 2007-06-12 2008-12-18 Coley Pharmaceutical Group, Inc. Quinazoline derivative useful as toll-like receptor antagonist
WO2009030996A1 (en) 2007-09-05 2009-03-12 Coley Pharmaceutical Group, Inc. Triazole compounds as toll-like receptor (tlr) agonists
JP5486602B2 (en) 2008-09-26 2014-05-07 エーザイ・アール・アンド・ディー・マネジメント株式会社 Benzoxazole compounds and methods of use
EP2340243B1 (en) 2008-10-17 2014-10-08 Boehringer Ingelheim International GmbH Heteroaryl substituted indole compounds useful as mmp-13 inhibitors
KR20110132564A (en) * 2009-02-11 2011-12-08 선오비온 파마슈티컬스 인코포레이티드 Histamine h3 inverse agonists and antagonists and methods of use thereof
BRPI1012097A2 (en) * 2009-06-10 2016-03-22 Sunovion Pharmaceuticals Inc h3 histamine antagonists and inverse antagonists and methods of their use.
WO2011009015A1 (en) 2009-07-16 2011-01-20 Mallinckrodt Inc. (+) - morphinans as antagonists of toll-like receptor 9 and therapeutic uses thereof
US9241991B2 (en) 2010-10-21 2016-01-26 The Brigham And Women's Hospital, Inc. Agents, compositions, and methods for treating pruritus and related skin conditions
MX346387B (en) 2011-01-12 2017-03-02 Ventirx Pharmaceuticals Inc Substituted benzoazepines as toll-like receptor modulators.
PT2663555T (en) 2011-01-12 2017-03-23 Array Biopharma Inc Substituted benzoazepines as toll-like receptor modulators
AU2012262021B2 (en) 2011-06-01 2016-07-28 Janus Biotherapeutics, Inc. Novel immune system modulators
BR112013030894A2 (en) 2011-06-01 2016-08-16 Janus Biotherapeutics Inc immune system modulators
JP6463631B2 (en) 2011-06-09 2019-02-06 ライゼン・ファーマシューティカルズ・エスアー Novel compounds as modulators of GPR-119
PL2731949T3 (en) * 2011-07-13 2018-10-31 Tiumbio Co., Ltd. 2-pyridyl substituted imidazoles as alk5 and/or alk4 inhibitors
WO2013052550A2 (en) 2011-10-04 2013-04-11 Janus Biotherapeutics, Inc. Novel imidazole quinoline-based immune system modulators
CN104302628B (en) 2012-05-18 2017-06-23 大日本住友制药株式会社 Carboxylic acid compound
JO3407B1 (en) 2012-05-31 2019-10-20 Eisai R&D Man Co Ltd Tetrahydropyrazolopyrimidine Compounds
CN106414432B (en) 2013-10-14 2019-06-14 卫材R&D管理有限公司 The quinoline compound selectively replaced
JP2016540013A (en) 2013-12-13 2016-12-22 武田薬品工業株式会社 Pyrrolo [3,2-C] pyridine derivatives as TLR inhibitors
JP2017525711A (en) 2014-08-22 2017-09-07 ジャナス バイオセラピューティクス，インク． Novel N2, N4, N7,6-tetrasubstituted pteridine-2,4,7-triamine and 2,4,6,7-tetrasubstituted pteridine compounds and methods for their synthesis and use
US9550778B2 (en) 2014-10-03 2017-01-24 Vanderbilt University Substituted 6-aryl-imidazopyridine and 6-aryl-triazolopyridine carboxamide analogs as negative allosteric modulators of mGluR5
MX2018001814A (en) 2015-08-13 2018-05-07 Merck Sharp & Dohme Cyclic di-nucleotide compounds as sting agonists.
US10071079B2 (en) 2016-06-29 2018-09-11 Bristol-Myers Squibb Company [1,2,4]triazolo[1,5-a]pyridinyl substituted indole compounds
IL263934B2 (en) 2016-06-29 2023-10-01 Hanmi Pharm Ind Co Ltd Glucagon derivative, conjugate thereof, composition comprising same and therapeutic use thereof
LT3478670T (en) 2016-06-29 2023-05-25 Kezar Life Sciences Crystalline salts of peptide epoxyketone immunoproteasome inhibitor
EP3490983B1 (en) 2016-07-30 2021-02-17 Bristol-Myers Squibb Company Dimethoxyphenyl substituted indole compounds as tlr7, tlr8 or tlr9 inhibitors
JP7028861B2 (en) 2016-09-09 2022-03-02 ブリストル－マイヤーズ スクイブ カンパニー Indole compound with pyridyl substitution
CN110997670B (en) 2017-08-04 2022-11-01 百时美施贵宝公司 [1,2,4] triazolo [4,3-a ] pyridyl substituted indole compounds
WO2019028302A1 (en) 2017-08-04 2019-02-07 Bristol-Myers Squibb Company Substituted indole compounds useful as inhibitors of tlr7/8/9
WO2019099336A1 (en) 2017-11-14 2019-05-23 Bristol-Myers Squibb Company Substituted indole compounds
KR20200100687A (en) 2017-12-15 2020-08-26 브리스톨-마이어스 스큅 컴퍼니 Substituted indole ether compounds
AR113959A1 (en) 2017-12-18 2020-07-01 Bristol Myers Squibb Co 4-AZAINDOL COMPOUNDS
KR20200101398A (en) 2017-12-19 2020-08-27 브리스톨-마이어스 스큅 컴퍼니 Amide substituted indole compounds useful as TLR inhibitors
EA202091508A1 (en) 2017-12-19 2020-09-14 Бристол-Маерс Сквибб Компани 6-AZAINDOL CONNECTIONS
ES2932361T3 (en) 2017-12-19 2023-01-18 Bristol Myers Squibb Co Substituted Indole Compounds Useful as TLR Inhibitors
MX2020006014A (en) 2017-12-20 2020-08-17 Bristol Myers Squibb Co Diazaindole compounds.
CN111491918B (en) 2017-12-20 2023-10-24 百时美施贵宝公司 Aryl and heteroaryl substituted indole compounds
CA3086431A1 (en) 2017-12-20 2019-06-27 Bristol-Myers Squibb Company Amino indole compounds useful as tlr inhibitors
CN112912382B (en) 2018-10-24 2024-07-02 百时美施贵宝公司 Substituted indole dimer compounds
JP2022505707A (en) 2018-10-24 2022-01-14 ブリストル－マイヤーズ スクイブ カンパニー Substituted indole and indazole compounds

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008065198A1 (en) * 2006-12-01 2008-06-05 Galapagos N.V. Triazolopyridine compounds useful for the treatment of degenerative & inflammatory diseases
CN101977910A (en) * 2008-01-22 2011-02-16 赛诺菲-安万特 N-azabicyclic carboxamide derivatives, preparation thereof and therapeutic use thereof
CN102482273A (en) * 2009-06-26 2012-05-30 加拉帕戈斯股份有限公司 5-phenyl-[1,2,4 ]triazolo[1,5-a]pyridin-2-yl carboxamides as jak inhibitors

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